Membrane Microdomain Disassembly Inhibits MRSA Antibiotic Resistance

Summary A number of bacterial cell processes are confined functional membrane microdomains (FMMs), structurally and functionally similar to lipid rafts of eukaryotic cells. How bacteria organize these intricate platforms and what their biological significance is remain important questions. Using the pathogen methicillin-resistant Staphylococcus aureus (MRSA), we show here that membrane-carotenoid interaction with the scaffold protein flotillin leads to FMM formation, which can be visualized using super-resolution array tomography. These membrane platforms accumulate multimeric protein complexes, for which flotillin facilitates efficient oligomerization. One of these proteins is PBP2a, responsible for penicillin resistance in MRSA. Flotillin mutants are defective in PBP2a oligomerization. Perturbation of FMM assembly using available drugs interferes with PBP2a oligomerization and disables MRSA penicillin resistance in vitro and in vivo, resulting in MRSA infections that are susceptible to penicillin treatment. Our study demonstrates that bacteria possess sophisticated cell organization programs and defines alternative therapies to fight multidrug-resistant pathogens using conventional antibiotics.
Graphical Abstract
Highlights • Staphyloxanthin and flotillin preferentially interact and accumulate in FMMs • FMMs facilitate efficient oligomerization of multimeric protein complexes • PBP2a, which confers β-lactam resistance on S. aureus, is harbored within FMMs • FMM disruption disables PBP2a oligomerization and thus, S. aureus antibiotic resistance
Using statins to disassemble bacterial membrane microdomains can decrease antibiotic resistance and re-sensitize MRSA to antibiotic therapies in vivo.