Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium
ABSTRACT 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 aureu...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-10-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.01412-22 |
| _version_ | 1811329715546357760 |
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| author | Shivani Gargvanshi William G. Gutheil |
| author_facet | Shivani Gargvanshi William G. Gutheil |
| author_sort | Shivani Gargvanshi |
| collection | DOAJ |
| description | ABSTRACT 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. |
| first_indexed | 2024-04-13T15:48:47Z |
| format | Article |
| id | doaj.art-97ee520ee24147d6b7ed7b858f0d2673 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-13T15:48:47Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-97ee520ee24147d6b7ed7b858f0d26732022-12-22T02:40:54ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-10-0110510.1128/spectrum.01412-22Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faeciumShivani Gargvanshi0William G. Gutheil1Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USADivision of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/spectrum.01412-22library screeningdrug repurposingsynergy screeningEnterococcus faeciummicrosomemetabolism |
| spellingShingle | Shivani Gargvanshi William G. Gutheil Library Screening for Synergistic Combinations of FDA-Approved Drugs and Metabolites with Vancomycin against VanA-Type Vancomycin-Resistant Enterococcus faecium Microbiology Spectrum library screening drug repurposing synergy screening Enterococcus faecium microsome metabolism |
| 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 | library screening drug repurposing synergy screening Enterococcus faecium microsome metabolism |
| url | https://journals.asm.org/doi/10.1128/spectrum.01412-22 |
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