A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus

Abstract

Significance: There is a critical lack of therapeutic agents to treat infections caused by nongrowing persister forms of methicillin-resistant Staphylococcus aureus (MRSA). Although membrane-disrupting agents can kill persister cells, their therapeutic potential has been mostly overlooked because of low selectivity for bacterial versus mammalian membranes. We report that the clinically approved anthelmintic drug bithionol kills MRSA persisters by disrupting membrane lipid bilayers at concentrations that exhibit low levels of toxicity to mammalian cells. The selectivity of bithionol results from the presence of cholesterol in mammalian but not in bacterial membranes. We also show that the antipersister potency of membrane-active antimicrobial agents correlates with their ability to increase membrane fluidity. Our results significantly enhance our understanding of bacterial membrane disruption and membrane selectivity.