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Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium

Antimicrobial resistance is a major public health threat, and there is an urgent need for new strategies to address this issue. In a recent study, a library screening strategy was developed in which an FDA-approved drug library was screened against methicillin-resistant Staphylococcus aureus (MRSA)...

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Autores principales: Gargvanshi, Shivani, Gutheil, William G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9603392/
https://www.ncbi.nlm.nih.gov/pubmed/35969069
http://dx.doi.org/10.1128/spectrum.01412-22
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author Gargvanshi, Shivani
Gutheil, William G.
author_facet Gargvanshi, Shivani
Gutheil, William G.
author_sort Gargvanshi, Shivani
collection PubMed
description Antimicrobial resistance is a major public health threat, and there is an urgent need for new strategies to address this issue. In a recent study, a library screening strategy was developed in which an FDA-approved drug library was screened against methicillin-resistant Staphylococcus aureus (MRSA) in both its original (unmetabolized [UM]) and its human liver microsome metabolized (postmetabolized [PM]) forms and in the absence and presence of a resistant-to antibiotic. This allows the identification of agents with active metabolites and agents that can act synergistically with the resistant-to antibiotic. In this study, this strategy is applied to VanA-type vancomycin-resistant Enterococcus faecium (VREfm) in the absence and presence of vancomycin. Thirteen drugs with minimum MICs that were ≤12.5 μM under any tested condition (UM/PM vs. −/+vancomycin) were identified. Seven of these appeared to act synergistically with vancomycin, and follow-up checkerboard analyses confirmed synergy (∑FICmin ≤0.5) for six of these. Ultimately four rifamycins, two pleuromutilins, mupirocin, and linezolid were confirmed as synergistic. The most synergistic agent was rifabutin (∑FICmin = 0.19). Linezolid, a protein biosynthesis inhibitor, demonstrated relatively weak synergy (∑FICmin = 0.5). Only mupirocin showed significantly improved activity after microsomal metabolism, indicative of a more active metabolite, but efforts to identify an active metabolite were unsuccessful. Spectra of activity of several hits and related agents were also determined. Gemcitabine showed activity against a number vancomycin-resistant E. faecium and E. faecalis strains, but this activity was substantially weaker than previously observed in MRSA. IMPORTANCE Resistance to currently used antibiotics poses a serious threat to public health. This study reports a complete screen of 1,000 FDA-approved drugs and their metabolites against vancomycin-resistant Enterococcus faecium (VREfm) in both the absence and presence of vancomycin. This identified potentially synergistic combinations of FDA-approved drugs with vancomycin, and a number of these were confirmed in follow-up checkerboard assays. Among intrinsically active FDA-approved drugs, gemcitabine was identified as having activity against a panel of VRE strains.
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spelling pubmed-96033922022-10-27 Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium Gargvanshi, Shivani Gutheil, William G. Microbiol Spectr Research Article Antimicrobial resistance is a major public health threat, and there is an urgent need for new strategies to address this issue. In a recent study, a library screening strategy was developed in which an FDA-approved drug library was screened against methicillin-resistant Staphylococcus aureus (MRSA) in both its original (unmetabolized [UM]) and its human liver microsome metabolized (postmetabolized [PM]) forms and in the absence and presence of a resistant-to antibiotic. This allows the identification of agents with active metabolites and agents that can act synergistically with the resistant-to antibiotic. In this study, this strategy is applied to VanA-type vancomycin-resistant Enterococcus faecium (VREfm) in the absence and presence of vancomycin. Thirteen drugs with minimum MICs that were ≤12.5 μM under any tested condition (UM/PM vs. −/+vancomycin) were identified. Seven of these appeared to act synergistically with vancomycin, and follow-up checkerboard analyses confirmed synergy (∑FICmin ≤0.5) for six of these. Ultimately four rifamycins, two pleuromutilins, mupirocin, and linezolid were confirmed as synergistic. The most synergistic agent was rifabutin (∑FICmin = 0.19). Linezolid, a protein biosynthesis inhibitor, demonstrated relatively weak synergy (∑FICmin = 0.5). Only mupirocin showed significantly improved activity after microsomal metabolism, indicative of a more active metabolite, but efforts to identify an active metabolite were unsuccessful. Spectra of activity of several hits and related agents were also determined. Gemcitabine showed activity against a number vancomycin-resistant E. faecium and E. faecalis strains, but this activity was substantially weaker than previously observed in MRSA. IMPORTANCE Resistance to currently used antibiotics poses a serious threat to public health. This study reports a complete screen of 1,000 FDA-approved drugs and their metabolites against vancomycin-resistant Enterococcus faecium (VREfm) in both the absence and presence of vancomycin. This identified potentially synergistic combinations of FDA-approved drugs with vancomycin, and a number of these were confirmed in follow-up checkerboard assays. Among intrinsically active FDA-approved drugs, gemcitabine was identified as having activity against a panel of VRE strains. American Society for Microbiology 2022-08-15 /pmc/articles/PMC9603392/ /pubmed/35969069 http://dx.doi.org/10.1128/spectrum.01412-22 Text en Copyright © 2022 Gargvanshi and Gutheil. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Gargvanshi, Shivani
Gutheil, William G.
Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium
title Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium
title_full Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium
title_fullStr Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium
title_full_unstemmed Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium
title_short Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium
title_sort library screening for synergistic combinations of fda-approved drugs and metabolites with vancomycin against vana-type vancomycin-resistant enterococcus faecium
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9603392/
https://www.ncbi.nlm.nih.gov/pubmed/35969069
http://dx.doi.org/10.1128/spectrum.01412-22
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