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

Abstract

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. 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.