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MICROBIOLOGY (292 journals)                  1 2 | Last

Showing 1 - 200 of 292 Journals sorted alphabetically
Access Microbiology     Open Access   (Followers: 1)
Acta Microbiologica et Immunologica Hungarica     Full-text available via subscription   (Followers: 5)
Acta Neurobiologiae Experimentalis     Open Access  
Advancements of Microbiology : Postępy Mikrobiologii     Open Access   (Followers: 3)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24)
Advances in Cell and Gene Therapy     Hybrid Journal   (Followers: 2)
Advances in Microbiology     Open Access   (Followers: 31)
Advances in Molecular Imaging     Open Access   (Followers: 1)
African Journal of Clinical and Experimental Microbiology     Open Access   (Followers: 4)
African Journal of Microbiology Research     Open Access   (Followers: 3)
Algorithms for Molecular Biology     Open Access   (Followers: 4)
American Journal of Current Microbiology     Open Access   (Followers: 6)
American Journal of Infectious Diseases and Microbiology     Open Access   (Followers: 31)
American Journal of Microbiological Research     Open Access   (Followers: 3)
American Journal of Molecular Biology     Open Access   (Followers: 4)
American Journal of Stem Cell Research     Open Access   (Followers: 6)
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 15)
Annals of Microbiology     Hybrid Journal   (Followers: 13)
Annual Review of Microbiology     Full-text available via subscription   (Followers: 51)
Antimicrobial Agents and Chemotherapy     Hybrid Journal   (Followers: 29)
Antiviral Research     Hybrid Journal   (Followers: 8)
Applied and Environmental Microbiology     Hybrid Journal   (Followers: 58)
Applied Biochemistry and Microbiology     Hybrid Journal   (Followers: 20)
Applied Microbiology and Biotechnology     Hybrid Journal   (Followers: 70)
Aquatic Microbial Ecology     Hybrid Journal   (Followers: 6)
Archives of Microbiology     Hybrid Journal   (Followers: 10)
Asian Journal of Biochemistry, Genetics and Molecular Biology     Open Access   (Followers: 1)
Avicenna Journal of Clinical Microbiology and Infection     Open Access   (Followers: 5)
Bacterial Empire     Open Access   (Followers: 1)
Bangladesh Journal of Medical Microbiology     Open Access   (Followers: 4)
Beneficial Microbes     Hybrid Journal   (Followers: 5)
Bio-Research     Full-text available via subscription   (Followers: 5)
BioArchitecture     Full-text available via subscription  
Bioethanol     Open Access  
Biofilm     Open Access   (Followers: 1)
Biomaterials Science     Full-text available via subscription   (Followers: 14)
Biomolecular and Health Science Journal     Open Access   (Followers: 1)
BioMolecular Concepts     Open Access   (Followers: 2)
Biomolecular Detection and Quantification     Open Access  
Biomolecules     Open Access   (Followers: 1)
Biotechnology and Molecular Biology Reviews     Open Access   (Followers: 3)
BMC Microbiology     Open Access   (Followers: 16)
Brazilian Journal of Microbiology     Open Access   (Followers: 5)
Canadian Journal of Infectious Diseases and Medical Microbiology     Open Access   (Followers: 8)
Canadian Journal of Microbiology     Hybrid Journal   (Followers: 7)
Cell Biology : Research & Therapy     Hybrid Journal   (Followers: 6)
Cell Biology and Development     Open Access   (Followers: 2)
Cell Host & Microbe     Full-text available via subscription   (Followers: 30)
Cell Medicine     Open Access   (Followers: 6)
Cell Regeneration     Open Access   (Followers: 2)
Cell Stem Cell     Full-text available via subscription   (Followers: 51)
Cell Surface     Open Access  
CellBio     Open Access  
Cells     Open Access   (Followers: 4)
Cellular & Molecular Immunology     Hybrid Journal   (Followers: 16)
Cellular and Molecular Life Sciences (CMLS)     Hybrid Journal   (Followers: 5)
Cellular Microbiology     Hybrid Journal   (Followers: 16)
Cheese: Chemistry, Physics and Microbiology     Full-text available via subscription   (Followers: 3)
Chimerism     Full-text available via subscription  
Clinical Microbiology and Infection     Hybrid Journal   (Followers: 32)
Clinical Microbiology Newsletter     Hybrid Journal   (Followers: 13)
Clinical Microbiology Reviews     Hybrid Journal   (Followers: 23)
Comparative Immunology, Microbiology and Infectious Diseases     Hybrid Journal   (Followers: 14)
Computational Molecular Bioscience     Open Access   (Followers: 2)
Critical Reviews in Microbiology     Hybrid Journal   (Followers: 16)
Current Clinical Microbiology Reports     Hybrid Journal   (Followers: 4)
Current Issues in Molecular Biology     Open Access   (Followers: 3)
Current Microbiology     Hybrid Journal   (Followers: 23)
Current Molecular Biology Reports     Hybrid Journal   (Followers: 1)
Current Opinion in Microbiology     Hybrid Journal   (Followers: 43)
Current Protocols in Cell Biology     Hybrid Journal  
Current Protocols in Immunology     Hybrid Journal  
Current Protocols in Microbiology     Hybrid Journal  
Current Regenerative Medicine     Hybrid Journal   (Followers: 1)
Current Research in Microbiology     Open Access   (Followers: 25)
Current Tissue Engineering     Hybrid Journal   (Followers: 4)
Current Tissue Microenvironment Reports     Hybrid Journal   (Followers: 2)
Current Topics in Microbiology and Immunology     Hybrid Journal   (Followers: 15)
Diagnostic Microbiology and Infectious Disease     Hybrid Journal   (Followers: 13)
Egyptian Journal of Biochemistry and Molecular Biology     Full-text available via subscription  
Emerging Microbes & Infections     Open Access   (Followers: 5)
Environmental Microbiology     Hybrid Journal   (Followers: 29)
Environmental Microbiology Reports     Hybrid Journal   (Followers: 8)
Enzyme and Microbial Technology     Hybrid Journal   (Followers: 12)
Epigenomes     Open Access  
European Journal of Clinical Microbiology & Infectious Diseases     Hybrid Journal   (Followers: 37)
European Journal of Microbiology and Immunology     Open Access   (Followers: 11)
European Journal of Molecular and Clinical Medicine     Open Access  
Experimental and Molecular Pathology     Hybrid Journal   (Followers: 5)
Experimental Cell Research     Hybrid Journal   (Followers: 5)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 19)
Fems Microbiology Letters     Hybrid Journal   (Followers: 29)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 38)
Fermentation     Open Access   (Followers: 3)
Folia Histochemica et Cytobiologica     Open Access  
Folia Microbiologica     Hybrid Journal   (Followers: 3)
Food Microbiology     Hybrid Journal   (Followers: 22)
Frontiers in Cell and Developmental Biology     Open Access   (Followers: 5)
Frontiers in Cellular and Infection Microbiology     Open Access   (Followers: 5)
Frontiers in Cellular Neuroscience     Open Access   (Followers: 8)
Frontiers in Microbiology     Open Access   (Followers: 26)
Frontiers in Molecular Neuroscience     Open Access   (Followers: 6)
Future Microbiology     Hybrid Journal   (Followers: 7)
Future Virology     Hybrid Journal   (Followers: 9)
Gene Expression     Full-text available via subscription   (Followers: 2)
Genetics and Molecular Research     Open Access   (Followers: 5)
Geomicrobiology Journal     Hybrid Journal   (Followers: 3)
Gut Microbes     Full-text available via subscription   (Followers: 11)
IAWA Journal     Hybrid Journal   (Followers: 1)
Indian Journal of Microbiology     Hybrid Journal   (Followers: 4)
Indian Journal of Pathology and Microbiology     Open Access   (Followers: 4)
Infection Ecology & Epidemiology     Open Access   (Followers: 7)
Inside the Cell     Open Access  
International Journal of Antimicrobial Agents     Hybrid Journal   (Followers: 10)
International Journal of Bioassays     Open Access   (Followers: 2)
International Journal of Biotechnology and Molecular Biology Research     Open Access   (Followers: 5)
International Journal of Food Microbiology     Hybrid Journal   (Followers: 20)
International Journal of Genetics and Molecular Biology     Open Access   (Followers: 2)
International Journal of Infection and Microbiology     Open Access   (Followers: 6)
International Journal of Medical Microbiology     Hybrid Journal   (Followers: 10)
International Journal of Molecular Medicine     Full-text available via subscription   (Followers: 5)
International Journal of Mycobacteriology     Open Access  
International Journal of Systematic and Evolutionary Microbiology     Full-text available via subscription   (Followers: 5)
International Journal of Virology and Molecular Biology     Open Access  
International Microbiology     Open Access   (Followers: 5)
Iranian Journal of Microbiology     Open Access   (Followers: 1)
Journal of Cell Science & Therapy     Open Access   (Followers: 1)
Journal of Microbial & Biochemical Technology     Open Access   (Followers: 3)
Journal of Advances in Microbiology     Open Access   (Followers: 1)
Journal of Applied Biology & Biotechnology     Open Access   (Followers: 4)
Journal of Applied Microbiology     Hybrid Journal   (Followers: 24)
Journal of Bacteriology     Hybrid Journal   (Followers: 29)
Journal of Basic Microbiology     Hybrid Journal   (Followers: 3)
Journal of Biochemistry and Molecular Biology Research     Open Access   (Followers: 1)
Journal of Biomolecular Structure and Dynamics     Hybrid Journal   (Followers: 2)
Journal of Bionanoscience     Full-text available via subscription  
Journal of Bone Marrow Research     Open Access   (Followers: 2)
Journal of Brewing and Distilling     Open Access   (Followers: 2)
Journal of Cell and Animal Biology     Open Access  
Journal of Cell Biology and Genetics     Open Access   (Followers: 2)
Journal of Cellular Neuroscience and Oxidative Stress     Open Access  
Journal of Clinical Microbiology     Hybrid Journal   (Followers: 43)
Journal of Clinical Microbiology and Biochemical Technology     Open Access   (Followers: 2)
Journal of Clinical Pathology     Hybrid Journal   (Followers: 13)
Journal of Cytology & Molecular Biology     Open Access   (Followers: 2)
Journal of Extracellular Vesicles     Open Access   (Followers: 4)
Journal of Food Microbiology     Open Access   (Followers: 9)
Journal of General and Molecular Virology     Open Access   (Followers: 1)
Journal of Global Antimicrobial Resistance     Hybrid Journal   (Followers: 3)
Journal of Immunology and Clinical Microbiology     Open Access   (Followers: 2)
Journal of Industrial Microbiology and Biotechnology     Hybrid Journal   (Followers: 19)
Journal of Medical Microbiology     Full-text available via subscription   (Followers: 6)
Journal of Medical Microbiology & Diagnosis     Open Access   (Followers: 1)
Journal of Microbiological Methods     Hybrid Journal   (Followers: 3)
Journal of Microbiology     Hybrid Journal   (Followers: 11)
Journal of Microbiology & Biology Education     Open Access   (Followers: 10)
Journal of Microbiology and Antimicrobials     Open Access   (Followers: 3)
Journal of Microbiology and Infectious Diseases     Open Access   (Followers: 2)
Journal of Microbiology Research     Open Access   (Followers: 12)
Journal of Micropalaeontology     Open Access   (Followers: 3)
Journal of Molecular Biochemistry     Open Access   (Followers: 5)
Journal of Molecular Biology and Biotechnology     Open Access  
Journal of Molecular Biology Research     Open Access   (Followers: 3)
Journal of Molecular Microbiology and Biotechnology     Full-text available via subscription   (Followers: 21)
Journal of Molecular Psychiatry     Open Access   (Followers: 9)
Journal of Morphology     Hybrid Journal   (Followers: 7)
Journal of Oncobiomarkers     Open Access   (Followers: 1)
Journal of Organic and Biomolecular Simulations     Open Access  
Journal of Pharmacy & Bioresources     Full-text available via subscription   (Followers: 4)
Journal of Plant Pathology & Microbiology     Open Access   (Followers: 3)
Journal of Proteome Science and Computational Biology     Open Access   (Followers: 2)
Journal of Regenerative Medicine and Tissue Engineering     Open Access   (Followers: 6)
Journal of Stem Cell Research and Tissue Engineering     Open Access  
Journal of The Academy of Clinical Microbiologists     Open Access  
Journal of the American Society of Brewing Chemists     Full-text available via subscription   (Followers: 3)
Journal of the Institute of Brewing     Free   (Followers: 4)
Journal of Transplantation & Stem Cell Biology     Open Access   (Followers: 1)
Journal of Tropical Microbiology and Biotechnology     Full-text available via subscription  
Jundishapur Journal of Microbiology     Open Access  
Letters In Applied Microbiology     Hybrid Journal   (Followers: 10)
Lilloa     Open Access   (Followers: 1)
Macrophage     Open Access  
MAP Kinase     Open Access   (Followers: 1)
Medical Mycology     Open Access   (Followers: 4)
Medicine in Microecology     Open Access   (Followers: 1)
Memórias do Instituto Oswaldo Cruz     Open Access  
Methods in Molecular Biology     Hybrid Journal   (Followers: 20)
Microbes and Health     Open Access   (Followers: 1)
Microbes and Infection     Full-text available via subscription   (Followers: 7)
Microbes and Infectious Disease     Open Access   (Followers: 1)
Microbial Biotechnology     Open Access   (Followers: 12)
Microbial Cell Factories     Open Access   (Followers: 7)
Microbial Drug Resistance     Hybrid Journal   (Followers: 3)
Microbial Ecology     Hybrid Journal   (Followers: 17)
Microbial Ecology in Health and Disease     Open Access   (Followers: 2)
Microbial Genomics     Open Access   (Followers: 1)
Microbial Informatics and Experimentation     Open Access   (Followers: 1)
Microbial Pathogenesis     Hybrid Journal   (Followers: 7)
Microbial Risk Analysis     Full-text available via subscription  
Microbiologia Medica     Open Access   (Followers: 2)

        1 2 | Last

Similar Journals
Journal Cover
Antimicrobial Agents and Chemotherapy
Journal Prestige (SJR): 2.291
Citation Impact (citeScore): 4
Number of Followers: 29  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0066-4804 - ISSN (Online) 1098-6596
Published by American Society for Microbiology Homepage  [17 journals]
  • Editorial Board [Masthead]
    • PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.masthead.64-6
      Issue No: Vol. 64, No. 6 (2020)
  • Spectrum of Beta-Lactamase Inhibition by the Cyclic Boronate QPX7728, an
           Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and
           Metallo-Beta-Lactamases: Enhancement of Activity of Multiple Antibiotics
           against Isogenic Strains Expressing Single Beta-Lactamases [Mechanisms of
    • Authors: Lomovskaya, O; Tsivkovski, R, Nelson, K, Rubio-Aparicio, D, Sun, D, Totrov, M, Dudley, M. N.
      Abstract: QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor, with potent inhibition of key serine and metallo-beta-lactamases being observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MICs of multiple antibiotics administered intravenously only (ceftazidime, piperacillin, cefepime, ceftolozane, and meropenem) and orally bioavailable antibiotics (ceftibuten, cefpodoxime, tebipenem) alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against panels of laboratory strains of Pseudomonas aeruginosa and Klebsiella pneumoniae expressing over 55 diverse serine and metallo-beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against strains expressing class A extended-spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with the beta-lactamase inhibition demonstrated in biochemical assays. It also inhibited both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) class C beta-lactamases and class D enzymes, including carbapenemases, such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo-beta-lactamases (NDM, VIM, CcrA, IMP, and GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs for a majority of the strains to the level observed for the control with the vector alone, indicative of complete beta-lactamase inhibition. The ultrabroad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00212-20
      Issue No: Vol. 64, No. 6 (2020)
  • A Novel Deletion Mutation in pmrB Contributes to Concurrent Colistin
           Resistance in Carbapenem-Resistant Escherichia coli Sequence Type 405 of
           Clinical Origin [Mechanisms of Resistance]
    • Authors: Wang, C.-H; Siu, L. K, Chang, F.-Y, Tsai, Y.-K, Lin, Y.-T, Chiu, S.-K, Huang, L.-Y, Lin, J.-C.
      Abstract: We report the first clinical Escherichia coli strain EC3000 with concomitant chromosomal colistin and carbapenem resistance. A novel in-frame deletion, 6-11 (RPISLR), in pmrB that contributes to colistin resistance was verified using recombinant DNA techniques. Although being less fit than the wild-type (WT) strain or EC3000 revertant (chromosomal replacement of WT pmrB in EC3000), a portion of serially passaged EC3000 strains preserving colistin resistance without selective pressure raises the concern for further spread.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00220-20
      Issue No: Vol. 64, No. 6 (2020)
  • Emergence of the Phenicol Exporter Gene fexA in Campylobacter coli and
           Campylobacter jejuni of Animal Origin [Letters]
    • Authors: Liu, D; Li, X, Wang, Y, Schwarz, S, Shen, J.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00240-20
      Issue No: Vol. 64, No. 6 (2020)
  • Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model
           [Clinical Therapeutics]
    • Authors: Almeida, D. V; Converse, P. J, Omansen, T. F, Tyagi, S, Tasneen, R, Kim, J, Nuermberger, E. L.
      Abstract: Telacebec (Q203) is a new antitubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture negative in 2 weeks. Combining Q203 with rifampin resulted in a relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF with clarithromycin, the current standard of care, for 4 weeks. The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2 to 10 mg/kg were culture negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2, and 10 mg/kg were culture negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics substudy revealed that Q203 doses of 2 to 10 mg/kg in mice produce plasma concentrations similar to those produced by 100 to 300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations. These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for a cure to ≤ 1 week (or 5 doses of 2 to 10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00259-20
      Issue No: Vol. 64, No. 6 (2020)
  • Fenbendazole Controls In Vitro Growth, Virulence Potential, and Animal
           Infection in the Cryptococcus Model [Experimental Therapeutics]
    • Authors: de Oliveira, H. C; Joffe, L. S, Simon, K. S, Castelli, R. F, Reis, F. C. G, Bryan, A. M, Borges, B. S, Medeiros, L. C. S, Bocca, A. L, Del Poeta, M, Rodrigues, M. L.
      Abstract: The human diseases caused by the fungal pathogens Cryptococcus neoformans and Cryptococcus gattii are associated with high indices of mortality and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anticryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anticryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anticryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anticryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mouse model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00286-20
      Issue No: Vol. 64, No. 6 (2020)
  • In Vitro and In Vivo Study on the Synergistic Effect of Minocycline and
           Azoles against Pathogenic Fungi [Susceptibility]
    • Authors: Gao, L; Sun, Y, Yuan, M, Li, M, Zeng, T.
      Abstract: In vitro and in vivo interactions of minocycline and azoles, including itraconazole, voriconazole, and posaconazole, against filamentous pathogenic fungi were investigated. A total of 56 clinical isolates were studied in vitro via broth microdilution checkerboard technique, including 20 strains of Aspergillus fumigatus, 7 strains of Aspergillus flavus, 16 strains of Exophiala dermatitidis, 10 strains of Fusarium solani, and 3 strain s of Fusarium oxysporum. The results revealed that minocycline did not exhibit any significant antifungal activity against any of the tested strains. However, favorable synergy of minocycline with itraconazole, voriconazole, or posaconazole was observed against 34 (61%), 28 (50%), and 38 (68%) isolates, respectively, including azole-resistant A. fumigatus and Fusarium spp. with inherently high MICs of azoles. Synergistic combinations resulted in 4-fold to 16-fold reduction of effective MICs of minocycline and azoles. No antagonism was observed. In vivo effects of minocycline-azole combinations were evaluated by survival assay in a Galleria mellonella model infected with E. dermatitidis strain BMU00034; F. solani strain FS9; and A. fumigatus strains AF293, AFR1, and AFR2. Minocycline acted synergistically with azoles and significantly increased larvae survival in all isolates (P < 0.001), including azole-resistant A. fumigatus and azole-inactive Fusarium spp. In conclusion, the results suggested that minocycline combined with azoles may help to enhance the antifungal susceptibilities of azoles against pathogenic fungi and had the potential to overcome azole resistance issues.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00290-20
      Issue No: Vol. 64, No. 6 (2020)
  • Complex Response of the CpxAR Two-Component System to {beta}-Lactams on
           Antibiotic Resistance and Envelope Homeostasis in Enterobacteriaceae
           [Mechanisms of Resistance]
    • Authors: Masi, M; Pinet, E, Pages, J.-M.
      Abstract: The Cpx stress response is widespread among Enterobacteriaceae. We previously reported a mutation in cpxA in a multidrug-resistant strain of Klebsiella aerogenes isolated from a patient treated with imipenem. This mutation yields a single-amino-acid substitution (Y144N) located in the periplasmic sensor domain of CpxA. In this work, we sought to characterize this mutation in Escherichia coli by using genetic and biochemical approaches. Here, we show that cpxAY144N is an activated allele that confers resistance to β-lactams and aminoglycosides in a CpxR-dependent manner, by regulating the expression of the OmpF porin and the AcrD efflux pump, respectively. We also demonstrate the effect of the intimate interconnection between the Cpx system and peptidoglycan integrity on the expression of an exogenous AmpC β-lactamase by using imipenem as a cell wall-active antibiotic or by inactivating penicillin-binding proteins. Moreover, our data indicate that the Y144N substitution abrogates the interaction between CpxA and CpxP and increases phosphotransfer activity on CpxR. Because the addition of a strong AmpC inducer such as imipenem is known to cause abnormal accumulation of muropeptides (disaccharide-pentapeptide and N-acetylglucosamyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamy-meso-diaminopimelic-acid-d-alanyl-d-alanine) in the periplasmic space, we propose these molecules activate the Cpx system by displacing CpxP from the sensor domain of CpxA. Altogether, these data could explain why large perturbations to peptidoglycans caused by imipenem lead to mutational activation of the Cpx system and bacterial adaptation through multidrug resistance. These results also validate the Cpx system, in particular, the interaction between CpxA and CpxP, as a promising therapeutic target.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00291-20
      Issue No: Vol. 64, No. 6 (2020)
  • Oral Fosfomycin Treatment for Enterococcal Urinary Tract Infections in a
           Dynamic In Vitro Model [Pharmacology]
    • Authors: Abbott, I. J; van Gorp, E, van der Meijden, A, Wijma, R. A, Meletiadis, J, Roberts, J. A, Mouton, J. W, Peleg, A. Y.
      Abstract: There are limited treatment options for enterococcal urinary tract infections, especially vancomycin-resistant Enterococcus (VRE). Oral fosfomycin is a potential option, although limited data are available guiding dosing and susceptibility. We undertook pharmacodynamic profiling of fosfomycin against E. faecalis and E. faecium isolates using a dynamic in vitro bladder infection model. Eighty-four isolates underwent fosfomycin agar dilution susceptibility testing (E. faecalis MIC50/90 32/64 μg/ml; E. faecium MIC50/90 64/128 μg/ml). Sixteen isolates (including E. faecalis ATCC 29212 and E. faecium ATCC 35667) were chosen to reflect the MIC range and tested in the bladder infection model with synthetic human urine (SHU). Under drug-free conditions, E. faecium demonstrated greater growth restriction in SHU compared to E. faecalis (E. faecium maximal growth 5.8 ± 0.6 log10 CFU/ml; E. faecalis 8.0 ± 1.0 log10 CFU/ml). Isolates were exposed to high and low fosfomycin urinary concentrations after a single dose, and after two doses given over two days with low urinary concentration exposure. Simulated concentrations closely matched the target (bias 2.3%). E. faecalis isolates required greater fosfomycin exposure for 3 log10 kill from the starting inoculum compared with E. faecium. The fAUC0-72/MIC and f%T> MIC0-72 for E. faecalis were 672 and 70%, compared to 216 and 51% for E. faecium, respectively. There was no rise in fosfomycin MIC postexposure. Two doses of fosfomycin with low urinary concentrations resulted in equivalent growth inhibition to a single dose with high urinary concentrations. With this urinary exposure, fosfomycin was effective in promoting suppression of regrowth (>3 log10 kill) in the majority of isolates.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00342-20
      Issue No: Vol. 64, No. 6 (2020)
  • Structural Recognition of Spectinomycin by Resistance Enzyme ANT(9) from
           Enterococcus faecalis [Mechanisms of Resistance]
    • Authors: Kanchugal P, S; Selmer, M.
      Abstract: Spectinomycin is a ribosome-binding antibiotic that blocks the translocation step of translation. A prevalent resistance mechanism is modification of the drug by aminoglycoside nucleotidyl transferase (ANT) enzymes of the spectinomycin-specific ANT(9) family or by enzymes of the dual-specificity ANT(3)(9) family, which also acts on streptomycin. We previously reported the structural mechanism of streptomycin modification by the ANT(3)(9) AadA from Salmonella enterica. ANT(9) from Enterococcus faecalis adenylates the 9-hydroxyl of spectinomycin. Here, we present the first structures of spectinomycin bound to an ANT enzyme. Structures were solved for ANT(9) in apo form, in complex with ATP, spectinomycin, and magnesium, or in complex with only spectinomycin. ANT(9) shows an overall structure similar to that of AadA, with an N-terminal nucleotidyltransferase domain and a C-terminal α-helical domain. Spectinomycin binds close to the entrance of the interdomain cleft, while ATP is buried at the bottom. Upon drug binding, the C-terminal domain rotates 14 degrees to close the cleft, allowing contacts of both domains with the drug. Comparison with AadA shows that spectinomycin specificity is explained by a straight α5 helix and a shorter α5-α6 loop, which would clash with the larger streptomycin substrate. In the active site, we observed two magnesium ions, one of them in a previously unobserved position that may activate the 9-hydroxyl for deprotonation by the catalytic base Glu-86. The observed binding mode for spectinomycin suggests that spectinamides and aminomethyl spectinomycins, recent spectinomycin analogues with expansions in position 4 of the C ring, are also subjected to modification by ANT(9) and ANT(3)(9) enzymes.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00371-20
      Issue No: Vol. 64, No. 6 (2020)
  • Imipenem Population Pharmacokinetics: Therapeutic Drug Monitoring Data
           Collected in Critically Ill Patients with or without Extracorporeal
           Membrane Oxygenation [Pharmacology]
    • Authors: Chen, W; Zhang, D, Lian, W, Wang, X, Du, W, Zhang, Z, Guo, D, Zhang, X, Zhan, Q, Li, P.
      Abstract: Carbapenem pharmacokinetic (PK) profiles are significantly different in critically ill patients because of the drastic variability of the patients’ physiological parameters. Published population PK studies have mainly focused on specific diseases, and the majority of these studies had small sample sizes. The aim of this study was to develop a population PK model of imipenem in critically ill patients that estimated the influence of various clinical and biological covariates and the use of extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). A two-compartment population PK model with creatinine clearance (CLCR), body weight (WT), and ECMO as fixed effects was developed using the nonlinear mixed-effects model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates based on the pharmacokinetic/pharmacodynamic index (f%T>MIC) for the range of clinically relevant MICs. The results showed that there may be insufficient drug use in the clinical routine drug dose regimen, and 750 mg every 6 h (q6h) could achieve a higher treatment success rate. The blood concentrations of imipenem in ECMO patients were lower than those in non-ECMO patients; therefore, dosages may need to be increased. The dosage may need adjustment for patients with a CLCR of ≤70 ml/min, but the dose should be lowered carefully to avoid the insufficient drug exposure. Dose adjustment is not necessary for patients with WT ranging from 50 to 80 kg. Due to the large variation in PK profile of imipenem in critically ill patients, therapeutic drug monitoring (TDM) should be carried out to optimize drug regimens.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00385-20
      Issue No: Vol. 64, No. 6 (2020)
  • Should In Vitro and In Vivo Studies on Antimicrobial Agents during
           Continuous Renal Replacement Therapy Comply with General Principles of
           Pharmacokinetics' [Letters]
    • Authors: Baud, F. J; Houze, P.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00388-20
      Issue No: Vol. 64, No. 6 (2020)
  • Reply to Baud and Houze, "Should In Vitro and In Vivo Studies on
           Antimicrobial Agents during Continuous Renal Replacement Therapy Comply
           with General Principles of Pharmacokinetics'" [Letters]
    • Authors: Wenzler, E; Biagi, M, Tan, X, Butler, D. A.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00401-20
      Issue No: Vol. 64, No. 6 (2020)
  • Updated Approaches against SARS-CoV-2 [Minireviews]
    • Authors: Li, H; Zhou, Y, Zhang, M, Wang, H, Zhao, Q, Liu, J.
      Abstract: Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lies behind the ongoing outbreak of coronavirus disease 2019 (COVID-19). There is a growing understanding of SARS-CoV-2 in virology, epidemiology, and clinical management strategies. However, no anti-SARS-CoV-2 drug or vaccine has been officially approved due to the absence of adequate evidence. Scientists are racing to develop a treatment for COVID-19. Recent studies have revealed many attractive therapeutic options, even if some of them remain to be further confirmed in rigorous preclinical models and clinical trials. In this minireview, we aim to summarize the updated potential approaches against SARS-CoV-2. We emphasize that further efforts are warranted to develop the safest and most effective approach.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00483-20
      Issue No: Vol. 64, No. 6 (2020)
  • Retraction for Huang et al., "Use of the Antimicrobial Peptide Pardaxin
           (GE33) To Protect against Methicillin-Resistant Staphylococcus aureus
           Infection in Mice with Skin Injuries" [Retraction]
    • Authors: Huang, H.-N; Pan, C.-Y, Chan, Y.-L, Chen, J.-Y, Wu, C.-J.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00484-20
      Issue No: Vol. 64, No. 6 (2020)
  • Nonclinical Pharmacokinetics, Protein Binding, and Elimination of
           KBP-7072, an Aminomethylcycline Antibiotic, in Animal Models
    • Authors: Tan, X; Zhang, M, Liu, Q, Wang, P, Zhou, T, Zhu, Y, Chen, B, Wang, M, Xia, Y, Benn, V, Yang, F, Zhang, J.
      Abstract: KBP-7072 is a semisynthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens, including multidrug-resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (i.v.) administrations of single and multiple doses were investigated in animal models, including during fed and fasted states, and the protein binding and excretion characteristics were also evaluated. In Sprague-Dawley (SD) rats, beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after the administration of single oral and i.v. and multiple oral doses. The oral bioavailability ranged from 12% to 32%. The mean time to maximum concentration (Tmax) ranged from 0.5 to 4 h, and the mean half-life ranged from approximately 6 to 11 h. The administration of oral doses in the fed state resulted in marked reductions in the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5-mg/kg oral dose of KBP-7072 in SD rats, the cumulative excretion in feces was 64% and that in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single- and multiple-ascending-dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once-daily oral and i.v. administration in clinical studies.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00488-20
      Issue No: Vol. 64, No. 6 (2020)
  • Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New
           Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and
           Metallo-Beta-Lactamases in Enterobacteriaceae, Pseudomonas aeruginosa, and
           Acinetobacter baumannii [Mechanisms of Resistance]
    • Authors: Lomovskaya, O; Nelson, K, Rubio-Aparicio, D, Tsivkovski, R, Sun, D, Dudley, M. N.
      Abstract: QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo-beta-lactamases at a nanomolar concentration range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impacts of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3-producing isogenic strains of Klebsiella pneumoniae and Pseudomonas aeruginosa and OXA-23-producing strains of Acinetobacter baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multidrug resistance efflux pumps either in Enterobacteriaceae or in nonfermenters, such as P. aeruginosa or A. baumannii. Against P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane was permeabilized. The potency of QPX7728 against P. aeruginosa was not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8- to 16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed the KPC-mediated meropenem resistance in strains with porin mutations, consistent with the lesser effect of these mutations on the potency of QPX7728 compared to that of other agents. The ultrabroad-spectrum beta-lactamase inhibition profile, combined with enhancement of the activity of multiple beta-lactam antibiotics with various sensitivities to the intrinsic resistance mechanisms of efflux and permeability, indicates that QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00552-20
      Issue No: Vol. 64, No. 6 (2020)
  • Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option
           for COVID-19 [Letters]
    • Authors: Hoffmann, M; Schroeder, S, Kleine-Weber, H, Müller, M. A, Drosten, C, Pöhlmann, S.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.00754-20
      Issue No: Vol. 64, No. 6 (2020)
  • In Vitro and In Vivo Characterization of Potent Antileishmanial Methionine
           Aminopeptidase 1 Inhibitors [Experimental Therapeutics]
    • Authors: Rodriguez, F; John, S. F, Iniguez, E, Montalvo, S, Michael, K, White, L, Liang, D, Olaleye, O. A, Maldonado, R. A.
      Abstract: Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL, and current drug regimens present several drawbacks, such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase 1 of L. major (MetAP1Lm), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activities of eight novel MetAP1 inhibitors (OJT001 to OJT008) were investigated. Three compounds, OJT006, OJT007, and OJT008, demonstrated potent antiproliferative effects in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect in transgenic L. major promastigotes overexpressing MetAP1Lm was diminished by almost 10-fold in comparison to the effect in wild-type promastigotes. Furthermore, the in vivo activities of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the footpad parasite load in the control group, OJT008 decreased the footpad parasite load significantly, by 86%, and exhibited no toxicity in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.01422-19
      Issue No: Vol. 64, No. 6 (2020)
  • OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis
           Activity as a DprE1 Inhibitor [Pharmacology]
    • Authors: Hariguchi, N; Chen, X, Hayashi, Y, Kawano, Y, Fujiwara, M, Matsuba, M, Shimizu, H, Ohba, Y, Nakamura, I, Kitamoto, R, Shinohara, T, Uematsu, Y, Ishikawa, S, Itotani, M, Haraguchi, Y, Takemura, I, Matsumoto, M.
      Abstract: There is an urgent need for new, potent antituberculosis (anti-TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3,4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent antituberculosis activity. The MICs of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 μg/ml. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for M. tuberculosis H37Rv was less than 1.91 x 10–7. It did not show antagonistic effects with other anti-TB agents in an in vitro checkerboard assay. Whole-genome and targeted sequencing of isolates resistant to OPC-167832 identified decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1), an essential enzyme for cell wall biosynthesis, as the target of the compound, and further studies demonstrated inhibition of DprE1 enzymatic activity by OPC-167832. In a mouse model of chronic TB, OPC-167832 showed potent bactericidal activities starting at a dose of 0.625 mg/kg of body weight. Further, it exhibited significant combination effects in 2-drug combinations with delamanid, bedaquiline, or levofloxacin. Finally, 3- or 4-drug regimens comprised of delamanid and OPC-167832 as the core along with bedaquiline, moxifloxacin, or linezolid showed efficacy in reducing the bacterial burden and preventing relapse superior to that of the standard treatment regimen. In summary, these results suggest that OPC-167832 is a novel and potent anti-TB agent, and regimens containing OPC-167832 and new or repurposed anti-TB drugs may have the potential to shorten the duration of treatment for TB.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02020-19
      Issue No: Vol. 64, No. 6 (2020)
  • A Histone Methyltransferase Inhibitor Can Reverse Epigenetically Acquired
           Drug Resistance in the Malaria Parasite Plasmodium falciparum [Mechanisms
           of Resistance]
    • Authors: Chan, A; Dziedziech, A, Kirkman, L. A, Deitsch, K. W, Ankarklev, J.
      Abstract: Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds, and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, and reversed acquired resistance to the antimalarial compound blasticidin S that is transported through PSACs. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02021-19
      Issue No: Vol. 64, No. 6 (2020)
  • Reconciling the Potentially Irreconcilable' Genotypic and Phenotypic
           Amoxicillin-Clavulanate Resistance in Escherichia coli [Mechanisms of
    • Authors: Davies, T. J; Stoesser, N, Sheppard, A. E, Abuoun, M, Fowler, P, Swann, J, Quan, T. P, Griffiths, D, Vaughan, A, Morgan, M, Phan, H. T. T, Jeffery, K. J, Andersson, M, Ellington, M. J, Ekelund, O, Woodford, N, Mathers, A. J, Bonomo, R. A, Crook, D. W, Peto, T. E. A, Anjum, M. F, Walker, A. S.
      Abstract: Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, and yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 Escherichia coli bloodstream infection isolates from Oxfordshire, United Kingdom, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). A total of 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity, 23% [78/339]) but improved when genetic features associated with penicillinase hyperproduction (e.g., promoter mutations and copy number estimates) were considered (sensitivity, 82% [277/339]; P < 0.0001). Most discrepancies occurred in isolates with MICs within ±1 doubling dilution of the breakpoint. We investigated two potential causes: the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02026-19
      Issue No: Vol. 64, No. 6 (2020)
  • Effect of Drug Pressure on Promoting the Emergence of
           Antimalarial-Resistant Parasites among Pregnant Women in Ghana [Mechanisms
           of Resistance]
    • Authors: Tornyigah, B; Coppee, R, Houze, P, Kusi, K. A, Adu, B, Quakyi, I, Coleman, N, Mama, A, Deloron, P, Anang, A. K, Clain, J, Tahar, R, Ofori, M. F, Tuikue Ndam, N.
      Abstract: The continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped Plasmodium falciparum resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple IRNI-A/FGKGS/T pfdhfr/pfdhps haplotypes, including the pfdhps A581G and A613S/T mutations, was high at delivery among post-SP treatment isolates (18.2%) compared to those of first antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine [IPTp-SP]; 6.1%; P = 0.03). Regarding the pfk13 marker gene, two nonsynonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast Asia. These mutations were predicted in silico to alter the stability of the pfk13 propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance of additional mutations associated with increased SP resistance as well as emergence of resistance against artemisinin derivatives.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02029-19
      Issue No: Vol. 64, No. 6 (2020)
  • An Engineered Double Lipid II Binding Motifs-Containing Lantibiotic
           Displays Potent and Selective Antimicrobial Activity against Enterococcus
           faecium [Chemistry; Biosynthesis]
    • Authors: Zhao, X; Yin, Z, Breukink, E, Moll, G. N, Kuipers, O. P.
      Abstract: Lipid II is an essential precursor for bacterial cell wall biosynthesis and thereby an important target for various antibiotics. Several lanthionine-containing peptide antibiotics target lipid II with lanthionine-stabilized lipid II binding motifs. Here, we used the biosynthesis system of the lantibiotic nisin to synthesize a two-lipid II binding motifs-containing lantibiotic, termed TL19, which contains the N-terminal lipid II binding motif of nisin and the distinct C-terminal lipid II binding motif of one peptide of the two-component haloduracin (i.e., HalA1). Further characterization demonstrated that (i) TL19 exerts 64-fold stronger antimicrobial activity against Enterococcus faecium than nisin(1-22), which has only one lipid II binding site, and (ii) both the N- and C-terminal domains are essential for the potent antimicrobial activity of TL19, as evidenced by mutagenesis of each single and the double domains. These results show the feasibility of a new approach to synthesize potent lantibiotics with two different lipid II binding motifs to treat specific antibiotic-resistant pathogens.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02050-19
      Issue No: Vol. 64, No. 6 (2020)
  • MK-571, a Cysteinyl Leukotriene Receptor 1 Antagonist, Inhibits Hepatitis
           C Virus Replication [Antiviral Agents]
    • Authors: Ruiz, I; Nevers, Q, Hernandez, E, Ahnou, N, Brillet, R, Softic, L, Donati, F, Berry, F, Hamadat, S, Fourati, S, Pawlotsky, J.-M, Ahmed-Belkacem, A.
      Abstract: The quinoline MK-571 is the most commonly used inhibitor of multidrug resistance protein-1 (MRP-1) but was originally developed as a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. While studying the modulatory effect of MRP-1 on anti-hepatitis C virus (HCV) direct-acting antiviral (DAA) efficiency, we observed an unexpected anti-HCV effect of compound MK-571 alone. This anti-HCV activity was characterized in Huh7.5 cells stably harboring a subgenomic genotype 1b replicon. A dose-dependent decrease of HCV RNA levels was observed upon MK-571 administration, with a 50% effective concentration (EC50 ± standard deviation) of 9 ± 0.3 μM and a maximum HCV RNA level reduction of approximatively 1 log10. MK-571 also reduced the replication of the HCV full-length J6/JFH1 model in a dose-dependent manner. However, probenecid and apigenin homodimer (APN), two specific inhibitors of MRP-1, had no effect on HCV replication. In contrast, the CysLTR1 antagonist SR2640 increased HCV-subgenomic replicon (SGR) RNA levels in a dose-dependent manner, with a maximum increase of 10-fold. In addition, a combination of natural CysLTR1 agonist (LTD4) or antagonists (zafirlukast, cinalukast, and SR2640) with MK-571 completely reversed its antiviral effect, suggesting its anti-HCV activity is related to CysLTR1 rather to MRP-1 inhibition. In conclusion, we showed that MK-571 inhibits HCV replication in hepatoma cell cultures by acting as a CysLTR1 receptor antagonist, thus unraveling a new host-virus interaction in the HCV life cycle.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02078-19
      Issue No: Vol. 64, No. 6 (2020)
  • Significant Efficacy of a Single Low Dose of Primaquine Compared to
           Stand-Alone Artemisinin Combination Therapy in Reducing Gametocyte
           Carriage in Cambodian Patients with Uncomplicated Multidrug-Resistant
           Plasmodium falciparum Malaria [Epidemiology and Surveillance]
    • Authors: Vantaux, A; Kim, S, Piv, E, Chy, S, Berne, L, Khim, N, Lek, D, Siv, S, Mukaka, M, Taylor, W. R, Menard, D.
      Abstract: Since 2012, a single low dose of primaquine (SLDPQ; 0.25 mg/kg of body weight) with artemisinin-based combination therapies has been recommended as the first-line treatment of acute uncomplicated Plasmodium falciparum malaria to interrupt its transmission, especially in low-transmission settings of multidrug resistance, including artemisinin resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and a lack of data on its efficacy. In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. The transmission-blocking efficacy of SLDPQ was evaluated on days 0, 1, 2, 3, 7, 14, 21, and 28, and recrudescence by reverse transcriptase PCR (RT-PCR) (gametocyte prevalence) and membrane feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP-SLDPQ reduced gametocyte carriage 3-fold compared to that achieved with DP. Of 48 patients tested on day 0, only 3 patients were infectious to mosquitoes (~6%). Posttreatment, three patients were infectious on day 14 (3.5%, 1/29) and on the 1st and 7th days of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission-blocking efficacy. Our study confirms the effective gametocyte clearance of SLDPQ when combined with DP in multidrug-resistant P. falciparum infections and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP, and ASMQ-SLDPQ has been deployed to treat all patients with symptomatic P. falciparum infections to further support the elimination of multidrug-resistant P. falciparum in Cambodia. (This study has been registered at under identifier NCT02434952.)
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02108-19
      Issue No: Vol. 64, No. 6 (2020)
  • Efficacy of Antibiotic Combinations against Multidrug-Resistant
           Pseudomonas aeruginosa in Automated Time-Lapse Microscopy and Static
           Time-Kill Experiments [Clinical Therapeutics]
    • Authors: Olsson, A; Wistrand-Yuen, P, Nielsen, E. I, Friberg, L. E, Sandegren, L, Lagerbäck, P, Tängden, T.
      Abstract: Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria, yet data regarding which combinations are most effective are lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa. We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampin, temocillin, thiamphenicol, or trimethoprim by automated time-lapse microscopy using predefined cutoff values indicating inhibition of growth (≤106 CFU/ml) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments. All strains were intermediate or resistant to polymyxin B, antipseudomonal β-lactams, ciprofloxacin, and amikacin. Genes encoding β-lactamases (e.g., blaPAO and blaOXA-50) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol, and trimethoprim. Time-kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem. Positive interactions were frequently found with the tested combinations, against strains that harbored several resistance mechanisms to the single drugs, and with antibiotics that are normally not active against P. aeruginosa. Further study is needed to explore the clinical utility of these combinations.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02111-19
      Issue No: Vol. 64, No. 6 (2020)
  • Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of
           Clostridioides difficile Infections [Experimental Therapeutics]
    • Authors: Abutaleb, N. S; Seleem, M. N.
      Abstract: Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for the treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and identified diiodohydroxyquinoline (DIHQ), an FDA-approved oral antiamoebic drug. DIHQ exhibited potent activity against 39 C. difficile isolates, inhibiting growth of 50% and 90% of these isolates at concentrations of 0.5 μg/ml and 2 μg/ml, respectively. In a time-kill assay, DIHQ was superior to vancomycin and metronidazole, reducing a high bacterial inoculum by 3 log10 within 6 h. Furthermore, DIHQ reacted synergistically with vancomycin and metronidazole against C. difficile in vitro. Moreover, at subinhibitory concentrations, DIHQ was superior to vancomycin and metronidazole in inhibiting two key virulence factors of C. difficile, toxin production and spore formation. Additionally, DIHQ did not inhibit the growth of key species that compose the host intestinal microbiota, such as Bacteroides, Bifidobacterium, and Lactobacillus spp. Collectively, our results indicate that DIHQ is a promising anticlostridial drug that warrants further investigation as a new therapeutic for CDIs.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02115-19
      Issue No: Vol. 64, No. 6 (2020)
  • Detection of Protein Aggregation in Live Plasmodium Parasites
    • Authors: Biosca, A; Bouzon-Arnaiz, I, Spanos, L, Siden-Kiamos, I, Iglesias, V, Ventura, S, Fernandez-Busquets, X.
      Abstract: The rapid evolution of resistance in the malaria parasite to every single drug developed against it calls for the urgent identification of new molecular targets. Using a stain specific for the detection of intracellular amyloid deposits in live cells, we have detected the presence of abundant protein aggregates in Plasmodium falciparum blood stages and female gametes cultured in vitro, in the blood stages of mice infected by Plasmodium yoelii, and in the mosquito stages of the murine malaria species Plasmodium berghei. Aggregated proteins could not be detected in early rings, the parasite form that starts the intraerythrocytic cycle. A proteomics approach was used to pinpoint actual aggregating polypeptides in functional P. falciparum blood stages, which resulted in the identification of 369 proteins, with roles particularly enriched in nuclear import-related processes. Five aggregation-prone short peptides selected from this protein pool exhibited different aggregation propensity according to Thioflavin-T fluorescence measurements, and were observed to form amorphous aggregates and amyloid fibrils in transmission electron microscope images. The results presented suggest that generalized protein aggregation might have a functional role in malaria parasites. Future antimalarial strategies based on the upsetting of the pathogen’s proteostasis and therefore affecting multiple gene products could represent the entry to new therapeutic approaches.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02135-19
      Issue No: Vol. 64, No. 6 (2020)
  • Rapid-Release Griffithsin Fibers for Dual Prevention of HSV-2 and HIV-1
           Infections [Antiviral Agents]
    • Authors: Tyo, K. M; Lasnik, A. B, Zhang, L, Jenson, A. B, Fuqua, J. L, Palmer, K. E, Steinbach-Rankins, J. M.
      Abstract: The biologic griffithsin (GRFT) has recently emerged as a candidate to safely prevent sexually transmitted infections (STIs), including human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus 2 (HSV-2). However, to date, there are few delivery platforms that are available to effectively deliver biologics to the female reproductive tract (FRT). The goal of this work was to evaluate rapid-release polyethylene oxide (PEO), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP) fibers that incorporate GRFT in in vitro (HIV-1 and HSV-2) and in vivo (HSV-2) infection models. GRFT loading was determined via enzyme-linked immunosorbent assay (ELISA), and the bioactivity of GRFT fibers was assessed using in vitro HIV-1 pseudovirus and HSV-2 plaque assays. Afterwards, the efficacy of GRFT fibers was assessed in a murine model of lethal HSV-2 infection. Finally, murine reproductive tracts and vaginal lavage samples were evaluated for histology and cytokine expression, 24 and 72 h after fiber administration, to determine safety. All rapid-release formulations achieved high levels of GRFT incorporation and were completely efficacious against in vitro HIV-1 and HSV-2 infections. Importantly, all rapid-release GRFT fibers provided potent protection in a murine model of HSV-2 infection. Moreover, histology and cytokine levels, evaluated from collected murine reproductive tissues and vaginal lavage samples treated with blank fibers, showed no increased cytokine production or histological aberrations, demonstrating the preliminary safety of rapid-release GRFT fibers in vaginal tissue.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02139-19
      Issue No: Vol. 64, No. 6 (2020)
  • Evaluation of the Effect of Contezolid (MRX-I) on the Corrected QT
           Interval in a Randomized, Double-Blind, Placebo- and Positive-Controlled
           Crossover Study in Healthy Chinese Volunteers [Clinical Therapeutics]
    • Authors: Wu, J; Cao, G, Wu, H, Chen, Y, Guo, B, Wu, X, Yu, J, Ni, K, Qian, J, Wang, L, Wu, J, Wang, Y, Yuan, H, Zhang, J, Xi, Y.
      Abstract: Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1,600 mg) dose, placebo, and oral moxifloxacin at 400 mg in four separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated. Time point analysis indicated that the upper bounds of the two-sided 90% confidence interval (CI) for placebo-corrected change-from-baseline QTc (QTc) were
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02158-19
      Issue No: Vol. 64, No. 6 (2020)
  • Impact of KPC Production and High-Level Meropenem Resistance on All-Cause
           Mortality of Ventilator-Associated Pneumonia in Association with
           Klebsiella pneumoniae [Clinical Therapeutics]
    • Authors: Rivera-Espinar, F; Machuca, I, Tejero, R, Rodriguez, J, Mula, A, Marfil, E, Cano, A, Gutierrez-Gutierrez, B, Rodriguez, M, Pozo, J. C, De la Fuente, C, Rodriguez-Bano, J, Martinez-Martinez, L, Leon, R, Torre-Cisneros, J.
      Abstract: Carbapenemase-producing Enterobacterales and specifically Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) are rapidly spreading worldwide. The prognosis of ventilator-associated pneumonia (VAP) caused by KPC-Kp is not well known. Our study tries to assess whether ventilator-associated pneumonia caused by a KPC-Kp strain is associated with higher all-cause mortality than that caused by carbapenem-susceptible isolates. This is a retrospective cohort study of patients with VAP due to K. pneumoniae from a 35-bed polyvalent intensive care unit in a university hospital (>40,000 annual admissions) between January 2012 and December 2016. Adjusted multivariate analysis was used to study the association of KPC-Kp with 30-day all-cause mortality (Cox regression). We analyze 69 cases of K. pneumoniae VAP, of which 39 were produced by a KPC-Kp strain with high-level resistance to meropenem (MIC> 16 mg/ml). All-cause mortality at 30 days was 41% in the KPC-Kp group (16/39) and 33.3% in the carbapenem-susceptible cases (10/30). KPC-Kp etiology was not associated with higher mortality when controlled for confounders (adjusted hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.46 to 3.41). Adequate targeted therapy (HR, 0.03; 95% CI,
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02164-19
      Issue No: Vol. 64, No. 6 (2020)
  • Proteomic Changes of Klebsiella pneumoniae in Response to Colistin
           Treatment and crrB Mutation-Mediated Colistin Resistance [Mechanisms of
    • Authors: Sun, L; Rasmussen, P. K, Bai, Y, Chen, X, Cai, T, Wang, J, Guo, X, Xie, Z, Ding, X, Niu, L, Zhu, N, You, X, Kirpekar, F, Yang, F.
      Abstract: Polymyxins are increasingly used as the critical last-resort therapeutic options for multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance has increased gradually over the past few years. Although studies on polymyxin mechanisms are expanding, systemwide analyses of the underlying mechanism for polymyxin resistance and stress response are still lacking. To understand how Klebsiella pneumoniae adapts to colistin (polymyxin E) pressure, we carried out proteomic analysis of a K. pneumoniae strain cultured with different concentrations of colistin. Our results showed that the proteomic responses to colistin treatment in K. pneumoniae involve several pathways, including (i) gluconeogenesis and the tricarboxylic acid (TCA) cycle, (ii) arginine biosynthesis, (iii) porphyrin and chlorophyll metabolism, and (iv) enterobactin biosynthesis. Interestingly, decreased abundances of class A β-lactamases, including TEM, SHV-11, and SHV-4, were observed in cells treated with colistin. Moreover, we present comprehensive proteome atlases of paired polymyxin-susceptible and -resistant K. pneumoniae strains. The polymyxin-resistant strain Ci, a mutant of K. pneumoniae ATCC BAA 2146, showed a missense mutation in crrB. This crrB mutant, which displayed lipid A modification with 4-amino-4-deoxy-l-arabinose (l-Ara4N) and palmitoylation, showed striking increases in the expression of CrrAB, PmrAB, PhoPQ, ArnBCADT, and PagP. We hypothesize that crrB mutations induce elevated expression of the arnBCADTEF operon and pagP via PmrAB and PhoPQ. Moreover, the multidrug efflux pump KexD, which was induced by crrB mutation, also contributed to colistin resistance. Overall, our results demonstrated proteomic responses to colistin treatment and the mechanism of CrrB-mediated colistin resistance, which may offer valuable information on the management of polymyxin resistance.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02200-19
      Issue No: Vol. 64, No. 6 (2020)
  • Stp1 Loss of Function Promotes {beta}-Lactam Resistance in Staphylococcus
           aureus That Is Independent of Classical Genes [Mechanisms of Resistance]
    • Authors: Chatterjee, A; Poon, R, Chatterjee, S. S.
      Abstract: β-Lactam resistance in Staphylococcus aureus limits treatment options. Stp1 and Stk1, a serine-threonine phosphatase and kinase, respectively, mediate serine-threonine kinase (STK) signaling. Loss-of-function point mutations in stp1 were detected among laboratory-passaged β-lactam-resistant S. aureus strains lacking mecA and blaZ, the major determinants of β-lactam resistance in the bacteria. Loss of Stp1 function facilitates β-lactam resistance of the bacteria.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02222-19
      Issue No: Vol. 64, No. 6 (2020)
  • Mutations in ArgS Arginine-tRNA Synthetase Confer Additional Antibiotic
           Tolerance Protection to Extended-Spectrum-{beta}-Lactamase-Producing
           Burkholderia thailandensis [Mechanisms of Resistance]
    • Authors: Yi, H; Park, J, Cho, K.-H, Kim, H. S.
      Abstract: Highly conserved PenI-type class A β-lactamase in pathogenic members of Burkholderia species can evolve to extended-spectrum β-lactamase (ESBL), which exhibits hydrolytic activity toward third-generation cephalosporins, while losing its activity toward the original penicillin substrates. We describe three single-amino-acid-substitution mutations in the ArgS arginine-tRNA synthetase that confer extra antibiotic tolerance protection to ESBL-producing Burkholderia thailandensis. This pathway can be exploited to evade antibiotic tolerance induction in developing therapeutic measures against Burkholderia species, targeting their essential aminoacyl-tRNA synthetases.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02252-19
      Issue No: Vol. 64, No. 6 (2020)
  • Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against
           Haemophilus influenzae Using a One-Compartment In Vitro Infection Model
    • Authors: VanScoy, B. D; Lakota, E. A, Conde, H, McCauley, J, Friedrich, L, Steenbergen, J. N, Ambrose, P. G, Bhavnani, S. M.
      Abstract: Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02265-19
      Issue No: Vol. 64, No. 6 (2020)
  • Ceftazidime-Avibactam Resistance Mediated by the N346Y Substitution in
           Various AmpC {beta}-Lactamases [Mechanisms of Resistance]
    • Authors: Compain, F; Debray, A, Adjadj, P, Dorchene, D, Arthur, M.
      Abstract: Chromosomal and plasmid-borne AmpC cephalosporinases are a major resistance mechanism to β-lactams in Enterobacteriaceae and Pseudomonas aeruginosa. The new β-lactamase inhibitor avibactam effectively inhibits class C enzymes and can fully restore ceftazidime susceptibility. The conserved amino acid residue Asn346 of AmpC cephalosporinases directly interacts with the avibactam sulfonate. Disruption of this interaction caused by the N346Y amino acid substitution in Citrobacter freundii AmpC was previously shown to confer resistance to the ceftazidime-avibactam combination (CAZ-AVI). The aim of this study was to phenotypically and biochemically characterize the consequences of the N346Y substitution in various AmpC backgrounds. Introduction of N346Y into Enterobacter cloacae AmpC (AmpCcloacae), plasmid-mediated DHA-1, and P. aeruginosa PDC-5 led to 270-, 12,000-, and 79-fold decreases in the inhibitory efficacy (k2/Ki) of avibactam, respectively. The kinetic parameters of AmpCcloacae and DHA-1 for ceftazidime hydrolysis were moderately affected by the substitution. Accordingly, AmpCcloacae and DHA-1 harboring N346Y conferred CAZ-AVI resistance (MIC of ceftazidime of 16 μg/ml in the presence of 4 μg/ml of avibactam). In contrast, production of PDC-5 N346Y was associated with a lower MIC (4 μg/ml) since this β-lactamase retained a higher inactivation efficacy by avibactam in comparison to AmpCcloacae N346Y. For FOX-3, the I346Y substitution did not reduce the inactivation efficacy of avibactam and the substitution was highly deleterious for β-lactam hydrolysis, including ceftazidime, preventing CAZ-AVI resistance. Since AmpCcloacae and DHA-1 display substantial sequence diversity, our results suggest that loss of hydrogen interaction between Asn346 and avibactam could be a common mechanism of acquisition of CAZ-AVI resistance.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02311-19
      Issue No: Vol. 64, No. 6 (2020)
  • Development of Probiotic Formulations for Oral Candidiasis Prevention:
           Gellan Gum as a Carrier To Deliver Lactobacillus paracasei 28.4
           [Experimental Therapeutics]
    • Authors: Ribeiro, F. d. C; Junqueira, J. C, dos Santos, J. D, de Barros, P. P, Rossoni, R. D, Shukla, S, Fuchs, B. B, Shukla, A, Mylonakis, E.
      Abstract: Probiotics might provide an alternative approach for the control of oral candidiasis. However, studies on the antifungal activity of probiotics in the oral cavity are based on the consumption of yogurt or other dietary products, and it is necessary to use appropriate biomaterials and specific strains to obtain probiotic formulations targeted for local oral administration. In this study, we impregnated gellan gum, a natural biopolymer used as a food additive, with a probiotic and investigated its antifungal activity against Candida albicans. Lactobacillus paracasei 28.4, a strain recently isolated from the oral cavity of a caries-free individual, was incorporated in several concentrations of gellan gum (0.6% to 1% [wt/vol]). All tested concentrations could incorporate L. paracasei cells while maintaining bacterial viability. Probiotic-gellan gum formulations were stable for 7 days when stored at room temperature or 4°C. Long-term storage of bacterium-impregnated gellan gum was achieved when L. paracasei 28.4 was lyophilized. The probiotic-gellan gum formulations provided a release of L. paracasei cells over 24 h that was sufficient to inhibit the growth of C. albicans, with effects dependent on the cell concentrations incorporated into gellan gum. The probiotic-gellan gum formulations also had inhibitory activity against Candida sp. biofilms by reducing the number of Candida sp. cells (P < 0.0001), decreasing the total biomass (P = 0.0003), and impairing hyphae formation (P = 0.0002), compared to the control group which received no treatment. Interestingly, a probiotic formulation of 1% (wt/vol) gellan gum provided an oral colonization of L. paracasei in mice with approximately 6 log CFU/ml after 10 days. This formulation inhibited C. albicans growth (P < 0.0001), prevented the development of candidiasis lesions (P = 0.0013), and suppressed inflammation (P = 0.0006) compared to the mice not treated in the microscopic analysis of the tongue dorsum. These results indicate that gellan gum is a promising biomaterial and can be used as a carrier system to promote oral colonization for probiotics that prevent oral candidiasis.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02323-19
      Issue No: Vol. 64, No. 6 (2020)
  • Comparison of Cefepime-Cefpirome and Carbapenem Therapy for Acinetobacter
           Bloodstream Infection in a Multicenter Study [Clinical Therapeutics]
    • Authors: Chang, Y.-Y; Yang, Y.-S, Wu, S.-L, Wang, Y.-C, Chen, T.-L, on behalf of the ACTION Study Group, Lee, Y.-T.
      Abstract: Carbapenems are currently the preferred agents for the treatment of serious Acinetobacter infections. However, whether cefepime-cefpirome can be used to treat an Acinetobacter bloodstream infection (BSI) if it is active against the causative pathogen(s) is not clear. This study aimed to compare the efficacy of cefepime-cefpirome and carbapenem monotherapy in patients with Acinetobacter BSI. The population included 360 patients with monomicrobial Acinetobacter BSI receiving appropriate antimicrobial therapy admitted to four medical centers in Taiwan in 2012 to 2017. The predictors of 30-day mortality were determined by Cox regression analysis. The overall 30-day mortality rate in the appropriate antibiotic treatment group was 25.0% (90/360 patients). The crude 30-day mortality rates for cefepime-cefpirome and carbapenem therapy were 11.5% (7/61 patients) and 26.3% (21/80 patients), respectively. The patients receiving cefepime-cefpirome or carbapenem therapy were infected by Acinetobacter nosocomialis (51.8%), Acinetobacter baumannii (18.4%), and Acinetobacter pittii (12.1%). After adjusting for age, Sequential Organ Failure Assessment (SOFA) score, invasive procedures, and underlying diseases, cefepime-cefpirome therapy was not independently associated with a higher or lower 30-day mortality rate compared to that with the carbapenem therapy. SOFA score (hazard ratio [HR], 1.324; 95% confidence interval [CI], 1.137 to 1.543; P < 0.001) and neutropenia (HR, 7.060; 95% CI, 1.607 to 31.019; P = 0.010) were independent risk factors for 30-day mortality of patients receiving cefepime-cefpirome or carbapenem monotherapy. The incidence densities of 30-day mortality for cefepime-cefpirome versus carbapenem therapy were 0.40% versus 1.04%, respectively. The therapeutic response of cefepime-cefpirome therapy was comparable to that with carbapenems among patients with Acinetobacter BSI receiving appropriate antimicrobial therapy.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02392-19
      Issue No: Vol. 64, No. 6 (2020)
  • ZN148 Is a Modular Synthetic Metallo-{beta}-Lactamase Inhibitor That
           Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo
           [Experimental Therapeutics]
    • Authors: Samuelsen, O; Astrand, O. A. H, Fröhlich, C, Heikal, A, Skagseth, S, Carlsen, T. J. O, Leiros, H.-K. S, Bayer, A, Schnaars, C, Kildahl-Andersen, G, Lauksund, S, Finke, S, Huber, S, Gjoen, T, Andresen, A. M. S, Okstad, O. A, Rongved, P.
      Abstract: Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in>98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ~30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02415-19
      Issue No: Vol. 64, No. 6 (2020)
  • Combination Therapy with Ibrexafungerp (Formerly SCY-078), a
           First-in-Class Triterpenoid Inhibitor of (1->3)-{beta}-D-Glucan Synthesis,
           and Isavuconazole for Treatment of Experimental Invasive Pulmonary
           Aspergillosis [Experimental Therapeutics]
    • Authors: Petraitis, V; Petraitiene, R, Katragkou, A, Maung, B. B. W, Naing, E, Kavaliauskas, P, Barat, S, Borroto-Esoda, K, Azie, N, Angulo, D, Walsh, T. J.
      Abstract: Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1->3)-β-d-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with antimold triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well-established persistently neutropenic New Zealand White (NZW) rabbit model of experimental IPA. Treatment groups included untreated control (UC) rabbits and rabbits receiving ibrexafungerp at 2.5 (SCY2.5) and 7.5 (SCY7.5) mg/kg of body weight/day, isavuconazole at 40 (ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced an in vitro synergistic interaction. There were significant in vivo reductions of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40 treatment groups versus those of the SCY2.5-treated, SCY7.5-treated, and UC (P < 0.01) groups. Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of the SCY2.5-, SCY7.5-, ISA40-treated, or UC (P < 0.05) groups. Serum galactomannan index (GMI) and (1->3)-β-d-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those of animals treated with SCY7.5 or ISA40 (P < 0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, and lower GMI and (1->3)-β-d-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an antimold triazole for treatment of IPA.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02429-19
      Issue No: Vol. 64, No. 6 (2020)
  • Metronidazole-Treated Porphyromonas gingivalis Persisters Invade Human
           Gingival Epithelial Cells and Perturb Innate Responses [Mechanisms of
    • Authors: Wang, C; Cheng, T, Li, X, Jin, L.
      Abstract: Periodontitis as a biofilm-associated inflammatory disease is highly prevalent worldwide. It severely affects oral health and yet closely links to systemic diseases like diabetes and cardiovascular disease. Porphyromonas gingivalis as a "keystone" periodontopathogen drives the shift of microbe-host symbiosis to dysbiosis and critically contributes to the pathogenesis of periodontitis. Persisters represent a tiny subset of biofilm-associated microbes highly tolerant to lethal treatment of antimicrobials, and, notably, metronidazole-tolerant P. gingivalis persisters have recently been identified by our group. This study further explored the interactive profiles of metronidazole-treated P. gingivalis persisters (M-PgPs) with human gingival epithelial cells (HGECs). P. gingivalis cells (ATCC 33277) at stationary phase were treated with a lethal dosage of metronidazole (100 μg/ml, 6 h) for generating M-PgPs. The interaction of M-PgPs with HGECs was assessed by microscopy, flow cytometry, cytokine profiling, and quantitative PCR (qPCR). We demonstrated that the overall morphology and ultracellular structure of M-PgPs remained unchanged. Importantly, M-PgPs maintained the capabilities to adhere to and invade HGECs. Moreover, M-PgPs significantly suppressed proinflammatory cytokine expression in HGECs at a level comparable to that seen with the untreated P. gingivalis cells, through the thermosensitive components. The present report reveals that P. gingivalis persisters induced by lethal treatment of antibiotics were able to maintain their capabilities to adhere to and invade human gingival epithelial cells and to perturb the innate host responses. Novel strategies and approaches need to be developed for tackling P. gingivalis and favorably modulating the dysregulated immunoinflammatory responses for oral/periodontal health and general well-being.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02529-19
      Issue No: Vol. 64, No. 6 (2020)
  • Antimicrobial Resistance in Clinical Ureaplasma spp. and Mycoplasma
           hominis and Structural Mechanisms Underlying Quinolone Resistance
           [Mechanisms of Resistance]
    • Authors: Yang, T; Pan, L, Wu, N, Wang, L, Liu, Z, Kong, Y, Ruan, Z, Xie, X, Zhang, J.
      Abstract: Antibiotic resistance is a global concern; however, data on antibiotic-resistant Ureaplasma spp. and Mycoplasma hominis are limited in comparison to similar data on other microbes. A total of 492 Ureaplasma spp. and 13 M. hominis strains obtained in Hangzhou, China, in 2018 were subjected to antimicrobial susceptibility testing for levofloxacin, moxifloxacin, erythromycin, clindamycin, and doxycycline using the broth microdilution method. The mechanisms underlying quinolone and macrolide resistance were determined. Meanwhile, a model of the topoisomerase IV complex bound to levofloxacin in wild-type Ureaplasma spp. was built to study the quinolone resistance mutations. For Ureaplasma spp., the levofloxacin, moxifloxacin, and erythromycin resistance rates were 84.69%, 51.44%, and 3.59% in U. parvum and 82.43%, 62.16%, and 5.40% in U. urealyticum, respectively. Of the 13 M. hominis strains, 11 were resistant to both levofloxacin and moxifloxacin, and five strains showed clindamycin resistance. ParC S83L was the most prevalent mutation in levofloxacin-resistant Ureaplasma strains, followed by ParE R448K. The two mutations GyrA S153L and ParC S91I were commonly identified in quinolone-resistant M. hominis. A molecular dynamics-refined structure revealed that quinolone resistance-associated mutations inhibited the interaction and reduced affinity with gyrase or topoisomerase IV and quinolones. The novel mutations S21A in the L4 protein and G2654T and T2245C in 23S rRNA and the ermB gene were identified in erythromycin-resistant Ureaplasma spp. As fluoroquinolone resistance in Ureaplasma spp. and Mycoplasma hominis remains high in China, the rational use of antibiotics needs to be further enhanced.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02560-19
      Issue No: Vol. 64, No. 6 (2020)
  • Ceftobiprole Activity against Bacteria from Skin and Skin Structure
           Infections in the United States from 2016 through 2018 [Susceptibility]
    • Authors: Flamm, R. K; Duncan, L. R, Hamed, K. A, Smart, J. I, Mendes, R. E, Pfaller, M. A.
      Abstract: Ceftobiprole medocaril is an advanced-generation cephalosporin prodrug that has qualified infectious disease product status granted by the US FDA and is currently being evaluated in phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSIs) and in patients with Staphylococcus aureus bacteremia. In this study, the activity of ceftobiprole and comparators was evaluated against more than 7,300 clinical isolates collected in the United States from 2016 through 2018 from patients with skin and skin structure infections. The major species/pathogen groups were S. aureus (53%), Enterobacterales (23%), Pseudomonas aeruginosa (7%), beta-hemolytic streptococci (6%), Enterococcus spp. (4%), and coagulase-negative staphylococci (2%). Ceftobiprole was highly active against S. aureus (MIC50/90, 0.5/1 mg/liter; 99.7% susceptible by EUCAST criteria; 42% methicillin-resistant S. aureus [MRSA]). Ceftobiprole also exhibited potent activity against other Gram-positive cocci. The overall susceptibility of Enterobacterales to ceftobiprole was 84.8% (>99.0% susceptible for isolate subsets that exhibited a non-extended-spectrum β-lactamase [ESBL] phenotype). A total of 74.4% of P. aeruginosa, 100% of beta-hemolytic streptococci and coagulase-negative staphylococci, and 99.6% of Enterococcus faecalis isolates were inhibited by ceftobiprole at ≤4 mg/liter. As expected, ceftobiprole was largely inactive against Enterobacterales that contained ESBL genes and Enterococcus faecium. Overall, ceftobiprole was highly active against most clinical isolates from the major Gram-positive and Gram-negative skin and skin structure pathogen groups collected at U.S. medical centers participating in the SENTRY Antimicrobial Surveillance Program during 2016 to 2018. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for a potential ABSSSI indication.
      PubDate: 2020-05-21T08:01:02-07:00
      DOI: 10.1128/AAC.02566-19
      Issue No: Vol. 64, No. 6 (2020)
  • The Als3 Cell Wall Adhesin Plays a Critical Role in Human Serum Amyloid
           A1-Induced Cell Death and Aggregation in Candida albicans [Mechanisms of
    • Authors: Gong, J; Bing, J, Guan, G, Nobile, C. J, Huang, G.
      Abstract: Antimicrobial peptides and proteins play critical roles in the host defense against invading pathogens. We recently discovered that recombinantly expressed human and mouse serum amyloid A1 (rhSAA1 and rmSAA1, respectively) proteins have potent antifungal activities against the major human fungal pathogen Candida albicans. At high concentrations, rhSAA1 disrupts C. albicans membrane integrity and induces rapid fungal cell death. In the present study, we find that rhSAA1 promotes cell aggregation and targets the C. albicans cell wall adhesin Als3. Inactivation of ALS3 in C. albicans leads to a striking decrease in cell aggregation and cell death upon rhSAA1 treatment, suggesting that Als3 plays a critical role in SAA1 sensing. We further demonstrate that deletion of the transcriptional regulators controlling the expression of ALS3, such as AHR1, BCR1, and EFG1, in C. albicans results in similar effects to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling indicates that rhSAA1 has a discernible impact on the expression of cell wall- and metabolism-related genes, suggesting that rhSAA1 treatment could lead to a nutrient starvation effect on C. albicans cells.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00024-20
      Issue No: Vol. 64, No. 6 (2020)
  • Comparison of Clinical Outcomes among Intensive Care Unit Patients
           Receiving One or Two Grams of Ceftriaxone Daily [Clinical Therapeutics]
    • Authors: Ackerman, A; Zook, N. R, Siegrist, J. F, Brummitt, C. F, Cook, M. M, Dilworth, T. J.
      Abstract: Intensive care unit (ICU) patients may experience ceftriaxone underexposure, but clinical outcomes data are lacking. The objective of this study was to determine the impact of ceftriaxone dosing on clinical outcomes among ICU patients without central nervous system (CNS) infection. A retrospective study of ICU patients receiving intravenous, empirical ceftriaxone for non-CNS infections was conducted. Patients ≥18 years of age who received ≤2 g of ceftriaxone daily for ≥72 h were included and categorized as receiving ceftriaxone 1 g or 2 g daily. The primary, composite outcome was treatment failure, defined as inpatient mortality and/or antibiotic escalation due to clinical worsening. Propensity score matching was performed based on the probability of receiving 2 g of ceftriaxone daily. Multivariable logistic regression determined the association between ceftriaxone dose and treatment failure in a propensity-matched cohort. A total of 212 patients were included in the propensity-matched cohort. The most common diagnoses (83.0%) were pneumonia and urinary tract infection. Treatment failure occurred in 17.0% and 5.7% of patients receiving 1 g and 2 g daily, respectively (P = 0.0156). Overall inpatient mortality was 8.5%. Ceftriaxone 2 g dosing was associated with a reduced likelihood of treatment failure (adjusted odds ratio [aOR] = 0.190; 95% confidence interval [CI] = 0.059 to 0.607). Other independent predictors of treatment failure included sequential organ failure assessment score (aOR = 1.440; 95% CI = 1.254 to 1.653) and creatinine clearance at 72 h from ceftriaxone initiation (aOR = 0.980; 95% CI = 0.971 to 0.999). Therefore, ceftriaxone at 2 g daily, when used as appropriate antimicrobial coverage, may be appropriate for ICU patients with lower mortality risk.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00066-20
      Issue No: Vol. 64, No. 6 (2020)
  • Pharmacokinetics-Pharmacodynamics of Enmetazobactam Combined with Cefepime
           in a Neutropenic Murine Thigh Infection Model [Pharmacology]
    • Authors: Bernhard, F; Odedra, R, Sordello, S, Cardin, R, Franzoni, S, Charrier, C, Belley, A, Warn, P, Machacek, M, Knechtle, P.
      Abstract: Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae are classified as critical priority pathogens, with extended-spectrum β-lactamases (ESBLs) as principal resistance determinants. Enmetazobactam (formerly AAI101) is a novel ESBL inhibitor developed in combination with cefepime for empirical treatment of serious Gram-negative infections in settings where ESBLs are prevalent. Cefepime-enmetazobactam has been investigated in a phase 3 trial in patients with complicated urinary tract infections or acute pyelonephritis. This study examined pharmacokinetic-pharmacodynamic (PK-PD) relationships of enmetazobactam, in combination with cefepime, for ESBL-producing isolates of Klebsiella pneumoniae in 26-h murine neutropenic thigh infection models. Enmetazobactam dose fractionation identified the time above a free threshold concentration (fT> CT) as the PK-PD index predictive of efficacy. Nine ESBL-producing isolates of K. pneumoniae, resistant to cefepime and piperacillin-tazobactam, were included in enmetazobactam dose-ranging studies. The isolates encoded CTX-M-type, SHV-12, DHA-1, and OXA-48 β-lactamases and covered a cefepime-enmetazobactam MIC range from 0.06 to 2 μg/ml. Enmetazobactam restored the efficacy of cefepime against all isolates tested. Sigmoid curve fitting across the combined set of isolates identified enmetazobactam PK-PD targets for stasis and for a 1-log10 bioburden reduction of 8% and 44% fT > 2 μg/ml, respectively, with a concomitant cefepime PK-PD target of 40 to 60% fT> cefepime-enmetazobactam MIC. These findings support clinical dose selection and breakpoint setting for cefepime-enmetazobactam.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00078-20
      Issue No: Vol. 64, No. 6 (2020)
  • Novel Ionophores Active against La Crosse Virus Identified through Rapid
           Antiviral Screening [Antiviral Agents]
    • Authors: Sandler, Z. J; Firpo, M. R, Omoba, O. S, Vu, M. N, Menachery, V. D, Mounce, B. C.
      Abstract: Bunyaviruses are significant human pathogens, causing diseases ranging from hemorrhagic fevers to encephalitis. Among these viruses, La Crosse virus (LACV), a member of the California serogroup, circulates in the eastern and midwestern United States. While LACV infection is often asymptomatic, dozens of cases of encephalitis are reported yearly. Unfortunately, no antivirals have been approved to treat LACV infection. Here, we developed a method to rapidly test potential antivirals against LACV infection. From this screen, we identified several potential antiviral molecules, including known antivirals. Additionally, we identified many novel antivirals that exhibited antiviral activity without affecting cellular viability. Valinomycin, a potassium ionophore, was among our top targets. We found that valinomycin exhibited potent anti-LACV activity in multiple cell types in a dose-dependent manner. Valinomycin did not affect particle stability or infectivity, suggesting that it may preclude virus replication by altering cellular potassium ions, a known determinant of LACV entry. We extended these results to other ionophores and found that the antiviral activity of valinomycin extended to other viral families, including bunyaviruses (Rift Valley fever virus, Keystone virus), enteroviruses (coxsackievirus, rhinovirus), flavirivuses (Zika virus), and coronaviruses (human coronavirus 229E [HCoV-229E] and Middle East respiratory syndrome CoV [MERS-CoV]). In all viral infections, we observed significant reductions in virus titer in valinomycin-treated cells. In sum, we demonstrate the importance of potassium ions to virus infection, suggesting a potential therapeutic target to disrupt virus replication.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00086-20
      Issue No: Vol. 64, No. 6 (2020)
  • Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against
           Mycobacterium abscessus in C3HeB/FeJ Mice [Experimental Therapeutics]
    • Authors: Le Moigne, V; Raynaud, C, Moreau, F, Dupont, C, Nigou, J, Neyrolles, O, Kremer, L, Herrmann, J.-L.
      Abstract: Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics, such as bedaquiline and imipenem, although in vitro data have questioned this combination. We report that the efficacy of bedaquiline-imipenem combination treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of M. abscessus. The addition of imipenem contributed to clearing the infection in the spleen.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00114-20
      Issue No: Vol. 64, No. 6 (2020)
  • Structure and Molecular Recognition Mechanism of IMP-13
           Metallo-{beta}-Lactamase [Mechanisms of Resistance]
    • Authors: Softley, C. A; Zak, K. M, Bostock, M. J, Fino, R, Zhou, R. X, Kolonko, M, Mejdi-Nitiu, R, Meyer, H, Sattler, M, Popowicz, G. M.
      Abstract: Multidrug resistance among Gram-negative bacteria is a major global public health threat. Metallo-β-lactamases (MBLs) target the most widely used antibiotic class, the β-lactams, including the most recent generation of carbapenems. Interspecies spread renders these enzymes a serious clinical threat, and there are no clinically available inhibitors. We present the crystal structures of IMP-13, a structurally uncharacterized MBL from the Gram-negative bacterium Pseudomonas aeruginosa found in clinical outbreaks globally, and characterize the binding using solution nuclear magnetic resonance spectroscopy and molecular dynamics simulations. The crystal structures of apo IMP-13 and IMP-13 bound to four clinically relevant carbapenem antibiotics (doripenem, ertapenem, imipenem, and meropenem) are presented. Active-site plasticity and the active-site loop, where a tryptophan residue stabilizes the antibiotic core scaffold, are essential to the substrate-binding mechanism. The conserved carbapenem scaffold plays the most significant role in IMP-13 binding, explaining the broad substrate specificity. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo-β-lactamase inhibitors, essential in the fight against antibiotic resistance.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00123-20
      Issue No: Vol. 64, No. 6 (2020)
  • MgrB Inactivation Is Responsible for Acquired Resistance to Colistin in
           Enterobacter hormaechei subsp. steigerwaltii [Mechanisms of Resistance]
    • Authors: Mhaya, A; Begu, D, Tounsi, S, Arpin, C.
      Abstract: Multidrug-resistant strains belonging to the Enterobacter cloacae complex (ECC) group, and especially those belonging to clusters C-III, C-IV, and C-VIII, have increasingly emerged as a leading cause of health care-associated infections, with colistin used as one of the last lines of treatment. However, colistin-resistant ECC strains have emerged. The aim of this study was to prove that MgrB, the negative regulator of the PhoP/PhoQ two-component regulatory system, is involved in colistin resistance in ECC of cluster C-VIII, formerly referred to as Enterobacter hormaechei subsp. steigerwaltii. An in vitro mutant (Eh22-Mut) was selected from a clinical isolate of Eh22. The sequencing analysis of its mgrB gene showed the presence of one nucleotide deletion leading to the formation of a truncated protein of six instead of 47 amino acids. The wild-type mgrB gene from Eh22 and that of a clinical strain of Klebsiella pneumoniae used as controls were cloned, and the corresponding recombinant plasmids were used for complementation assays. The results showed a fully restored susceptibility to colistin and confirmed for the first time that mgrB gene expression plays a key role in acquired resistance to colistin in ECC strains.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00128-20
      Issue No: Vol. 64, No. 6 (2020)
  • Biochemical Characterization of QPX7728, a New Ultrabroad-Spectrum
           Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases [Mechanisms
           of Resistance]
    • Authors: Tsivkovski, R; Totrov, M, Lomovskaya, O.
      Abstract: QPX7728 is a new ultrabroad-spectrum inhibitor of serine and metallo-beta-lactamases (MBLs) from a class of cyclic boronates that gave rise to vaborbactam. The spectrum and mechanism of beta-lactamase inhibition by QPX7728 were assessed using purified enzymes from all molecular classes. QPX7728 inhibits class A extended-spectrum beta-lactamases (ESBLs) (50% inhibitory concentration [IC50] range, 1 to 3 nM) and carbapenemases such as KPC (IC50, 2.9 ± 0.4 nM) as well as class C P99 (IC50 of 22 ± 8 nM) with a potency that is comparable to or higher than recently FDA-approved beta-lactamase inhibitors (BLIs) avibactam, relebactam, and vaborbactam. Unlike those other BLIs, QPX7728 is also a potent inhibitor of class D carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/58, IC50 range, 1 to 2 nM) as well as MBLs such as NDM-1 (IC50, 55 ± 25 nM), VIM-1 (IC50, 14 ± 4 nM), and IMP-1 (IC50, 610 ± 70 nM). Inhibition of serine enzymes by QPX7728 is associated with progressive inactivation with a high-efficiency k2/K ranging from 6.3 x 104 (for P99) to 9.9 x 105 M–1 s–1 (for OXA-23). This inhibition is reversible with variable stability of the QPX7728-beta-lactamase complexes with target residence time ranging from minutes to several hours: 5 to 20 min for OXA carbapenemases from A. baumannii, ~50 min for OXA-48, and 2 to 3 h for KPC and CTX-M-15. QPX7728 inhibited all tested serine enzymes at a 1:1 molar ratio. Metallo-beta-lactamases NDM, VIM, and IMP were inhibited by a competitive mechanism with fast-on–fast-off kinetics, with Kis of 7.5 ± 2.1 nM, 32 ± 14 nM, and 240 ± 30 nM for VIM-1, NDM-1, and IMP-1, respectively. QPX7728’s ultrabroad spectrum of BLI inhibition combined with its high potency enables combinations with multiple different beta-lactam antibiotics.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00130-20
      Issue No: Vol. 64, No. 6 (2020)
  • Population Pharmacokinetics and Dosage Optimization of Linezolid in
           Patients with Liver Dysfunction [Pharmacology]
    • Authors: Zhang, S.-h; Zhu, Z.-y, Chen, Z, Li, Y, Zou, Y, Yan, M, Xu, Y, Wang, F, Liu, M.-z, Zhang, M, Zhang, B.-k.
      Abstract: Linezolid is the first synthetic oxazolidone agent to treat infections caused by Gram-positive pathogens. Infected patients with liver dysfunction (LD) are more likely to suffer from adverse reactions, such as thrombocytopenia, when standard-dose linezolid is used than patients with LD who did not use linezolid. Currently, pharmacokinetics data of linezolid in patients with LD are limited. This study aimed to characterize pharmacokinetics parameters of linezolid in patients with LD, identify the factors influencing the pharmacokinetics, and propose an optimal dosage regimen. We conducted a prospective study and established a population pharmacokinetics model with the Phoenix NLME software. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and prediction corrected-visual predictive check. A total of 163 concentration samples from 45 patients with LD were adequately described by a one-compartment model with first-order elimination along with prothrombin activity (PTA) and creatinine clearance as significant covariates. Linezolid clearance (CL) was 2.68 liters/h (95% confidence interval [CI], 2.34 to 3.03 liters/h); the volume of distribution (V) was 58.34 liters (95% CI, 48.00 to 68.68 liters). Model-based simulation indicated that the conventional dose was at risk for overexposure in patients with LD or severe renal dysfunction; reduced dosage (300 mg/12 h) would be appropriate to achieve safe (minimum steady-state concentration [Cmin,ss] at 2 to 8 μg/ml) and effective targets (the ratio of area under the concentration-time curve from 0 to 24 h [AUC0–24] at steady state to MIC, 80 to 100). In addition, for patients with severe LD (PTA, ≤20%), the dosage (400 mg/24 h) was sufficient at an MIC of ≤2 μg/ml. This study recommended therapeutic drug monitoring for patients with LD. (This study has been registered in the Chinese Clinical Trial Registry under no. ChiCTR1900022118.)
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00133-20
      Issue No: Vol. 64, No. 6 (2020)
  • Transferable Resistance Gene optrA in Enterococcus faecalis from Swine in
           Brazil [Mechanisms of Resistance]
    • Authors: Almeida, L. M; Lebreton, F, Gaca, A, Bispo, P. M, Saavedra, J. T, Calumby, R. N, Grillo, L. M, Nascimento, T. G, Filsner, P. H, Moreno, A. M, Gilmore, M. S.
      Abstract: OptrA is an ATP-binding cassette (ABC)-F protein that confers resistance to oxazolidinones and phenicols and can be either plasmid-encoded or chromosomally encoded. Here, we isolated 13 Enterococcus faecalis strains possessing a linezolid MIC of ≥4 mg/liter from nursery pigs in swine herds located across Brazil. Genome sequence comparison showed that these strains possess optrA in different genetic contexts occurring in 5 different E. faecalis sequence type backgrounds. The optrA gene invariably occurred in association with an araC regulator and a gene encoding a hypothetical protein. In some contexts, this genetic island was able to excise and form a covalently closed circle within the cell; this circle appeared to occur in high abundance and to be transmissible by coresident plasmids.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00142-20
      Issue No: Vol. 64, No. 6 (2020)
  • Toward Harmonization of Voriconazole CLSI and EUCAST Breakpoints for
           Candida albicans Using a Validated In Vitro
           Pharmacokinetic/Pharmacodynamic Model [Susceptibility]
    • Authors: Beredaki, M.-I; Georgiou, P.-C, Siopi, M, Kanioura, L, Andes, D, Arendrup, M. C, Mouton, J. W, Meletiadis, J.
      Abstract: CLSI and EUCAST susceptibility breakpoints for voriconazole and Candida albicans differ by one dilution (≤0.125 and ≤0.06 mg/liter, respectively) whereas the epidemiological cutoff values for EUCAST (ECOFF) and CLSI (ECV) are the same (0.03 mg/liter). We therefore determined the pharmacokinetic/pharmacodynamic (PK/PD) breakpoints of voriconazole against C. albicans for both methodologies with an in vitro PK/PD model, which was validated using existing animal PK/PD data. Four clinical wild-type and non-wild-type C. albicans isolates (voriconazole MICs, 0.008 to 0.125 mg/liter) were tested in an in vitro PK/PD model. For validation purposes, mouse PK were simulated and in vitro PD were compared with in vivo outcomes. Human PK were simulated, and the exposure-effect relationship area under the concentration-time curve for the free, unbound fraction of a drug from 0 to 24 h (fAUC0–24)/MIC was described for EUCAST and CLSI 24/48-h methods. PK/PD breakpoints were determined using the fAUC0–24/MIC associated with half-maximal activity (EI50) and Monte Carlo simulation analysis. The in vitro 24-h PD EI50 values of voriconazole against C. albicans were 2.5 to 5 (1.5 to 17) fAUC/MIC. However, the 72-h PD were higher at 133 (51 to 347) fAUC/MIC for EUCAST and 94 (35 to 252) fAUC/MIC for CLSI. The mean (95% confidence interval) probability of target attainment (PTA) was 100% (95 to 100%), 97% (72 to 100%), 83% (35 to 99%), and 49% (8 to 91%) for EUCAST and 100% (97 to 100%), 99% (85 to 100%), 91% (52 to 100%), and 68% (17 to 96%) for CLSI for MICs of 0.03, 0.06, 0.125, and 0.25 mg/liter, respectively. Significantly,>95% PTA values were found for EUCAST/CLSI MICs of ≤0.03 mg/liter. For MICs of 0.06 to 0.125 mg/liter, trough levels 1 to 4 mg/liter would be required to attain the PK/PD target. A PK/PD breakpoint of C. albicans voriconazole at the ECOFF/ECV of 0.03 mg/liter was determined for both the EUCAST and CLSI methods, indicating the need for breakpoint harmonization for the reference methodologies.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00170-20
      Issue No: Vol. 64, No. 6 (2020)
  • Novel Peptide from Commensal Staphylococcus simulans Blocks
           Methicillin-Resistant Staphylococcus aureus Quorum Sensing and Protects
           Host Skin from Damage [Mechanisms of Action]
    • Authors: Brown, M. M; Kwiecinski, J. M, Cruz, L. M, Shahbandi, A, Todd, D. A, Cech, N. B, Horswill, A. R.
      Abstract: Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) on healthy skin. Evidence suggests that CoNS actively shape the skin immunological and microbial milieu to resist colonization or infection by opportunistic pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), in a variety of mechanisms collectively termed colonization resistance. One potential colonization resistance mechanism is the application of quorum sensing, also called the accessory gene regulator (agr) system, which is ubiquitous among staphylococci. Common and rare CoNS make autoinducing peptides (AIPs) that function as MRSA agr inhibitors, protecting the host from invasive infection. In a screen of CoNS spent media, we found that Staphylococcus simulans, a rare human skin colonizer and frequent livestock colonizer, released potent inhibitors of all classes of MRSA agr signaling. We identified three S. simulans agr classes and have shown intraspecies cross talk between noncognate S. simulans agr types for the first time. The S. simulans AIP-I structure was confirmed, and the novel AIP-II and AIP-III structures were solved via mass spectrometry. Synthetic S. simulans AIPs inhibited MRSA agr signaling with nanomolar potency. S. simulans in competition with MRSA reduced dermonecrotic and epicutaneous skin injury in murine models. The addition of synthetic AIP-I also effectively reduced MRSA dermonecrosis and epicutaneous skin injury in murine models. These results demonstrate potent anti-MRSA quorum sensing inhibition by a rare human skin commensal and suggest that cross talk between CoNS and MRSA may be important in maintaining healthy skin homeostasis and preventing MRSA skin damage during colonization or acute infection.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00172-20
      Issue No: Vol. 64, No. 6 (2020)
  • Fosmanogepix (APX001) Is Effective in the Treatment of Pulmonary Murine
           Mucormycosis Due to Rhizopus arrhizus [Experimental Therapeutics]
    • Authors: Gebremariam, T; Alkhazraji, S, Alqarihi, A, Wiederhold, N. P, Shaw, K. J, Patterson, T. F, Filler, S. G, Ibrahim, A. S.
      Abstract: Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, a protein involved in an early step in the conserved glycosylphosphotidyl inositol (GPI) posttranslational modification pathway of surface proteins in eukaryotic cells. Inhibition of fungal inositol acylation by MGX results in pleiotropic effects, including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here, we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 μg/ml) and low (0.25 μg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-life of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 postinfection compared to placebo. In addition, administration of fosmanogepix resulted in a 1 to 2 log reduction in both lung and brain fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first-in-class treatment for invasive mucormycosis.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00178-20
      Issue No: Vol. 64, No. 6 (2020)
  • Pharmacodynamics of Cefepime Combined with the Novel
           Extended-Spectrum-{beta}-Lactamase (ESBL) Inhibitor Enmetazobactam for
           Murine Pneumonia Caused by ESBL-Producing Klebsiella pneumoniae
    • Authors: Johnson, A; McEntee, L, Farrington, N, Kolamunnage-Dona, R, Franzoni, S, Vezzelli, A, Massimiliano, M, Knechtle, P, Belley, A, Dane, A, Drusano, G, Das, S, Hope, W.
      Abstract: Klebsiella pneumoniae strains that produce extended-spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options, and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for the treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose-ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing the area under the concentration-time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime, given as 100 mg/kg of body weight every 8 h intravenously (q8h i.v.), had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam, a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. The dose fractionation study suggested both fT> threshold and fAUC:MIC are relevant PD indices. The AUCELF:AUCplasma ratio for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT> MIC of ≥20% and enmetazobactam fT> 2 mg/liter of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.
      PubDate: 2020-05-21T08:01:01-07:00
      DOI: 10.1128/AAC.00180-20
      Issue No: Vol. 64, No. 6 (2020)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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