Ramoplanin at Bactericidal Concentrations Induces Bacterial Membrane Depolarization in Staphylococcus aureus

Abstract

ABSTRACTRamoplanin is an actinomycetes-derived antibiotic with broad-spectrum activity against Gram-positive bacteria that has been evaluated in clinical trials for the treatment of gastrointestinal vancomycin-resistant enterococci (VRE) andClostridium difficileinfections. Recent studies have proposed that ramoplanin binds to bacterial membranes as a C2symmetrical dimer that can sequester Lipid II, which causes inhibition of cell wall peptidoglycan biosynthesis and cell death. In this study, ramoplanin was shown to bind to anionic and zwitterionic membrane mimetics with a higher affinity for anionic membranes and to induce membrane depolarization of methicillin-susceptibleStaphylococcus aureus(MSSA) ATCC 25923 at concentrations at or above the minimal bactericidal concentration (MBC). The ultrastructural effects of ramoplanin onS. aureuswere also examined by transmission electron microscopy (TEM), and this showed dramatic changes to bacterial cell morphology. The correlation observed between membrane depolarization and bacterial cell viability suggests that this mechanism may contribute to the bactericidal activity of ramoplanin.