A Cell-Free Screen for Bacterial Membrane Disruptors Identifies Mefloquine as a Novel Antibiotic Adjuvant

Antibacterial discovery efforts have lagged far behind the need for new antibiotics. An approach that has gained popularity recently is targeting bacterial phospholipid membranes. We leveraged the differences between bacterial and mammalian phospholipid compositions to develop a high-throughput screen that identifies agents that selectively disrupt bacterial membranes while leaving mammalian membranes intact. This approach was used to screen 4480 compounds representing a subset of the Maybridge HitFinder^TM V.11 Collection and the Prestwick Chemical Drug Library^®. The screen identified 35 "positives" (0.8% hit rate) that preferentially damage bacterial model membranes. Among these, an antimalarial compound, mefloquine, and an aminoglycoside, neomycin, were identified. Further investigation of mefloquine's activity against Staphylococcus aureus showed that it has little antibiotic activity on its own but can alter membrane fluidity, thereby potentiating a β-lactam antibiotic, oxacillin, against both methicillin-susceptible and methicillin-resistant S. aureus. This study indicates that our cell-free screening approach is a promising platform for discovering bacterial membrane disruptors as antibacterials antibiotic adjuvants.