Membrane Microdomain Disassembly Inhibits MRSA Antibiotic Resistance

Abstract

SummaryA 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.

Photo‐Disassembly of Membrane Microdomains Revives Conventional Antibiotics against MRSA

“…The triplet excitons form with high yield via singlet fission when carotenoids self‐assemble into multimer or aggregates on cell membrane . As the triplet lifetime of STX is on a microsecond scale and STX laterally assembles within FMM, a nanosecond pulsed laser with high peak power can be used to effectively populate STX molecules to their triplet state within single pulse excitation thus accelerating STX photolysis nonlinearly.…”

“…This pigment is expressed specifically in S. aureus for bacterial pathogenesis and used as an antioxidant to neutralize reactive oxygen species (ROS) produced by the host immune system . Recent studies on cell membrane organization further suggest that STX and its derivatives condense as the constituent lipids of functional membrane microdomains (FMM), endowing membrane integrity and providing a platform to facilitate protein–protein oligomerization and interaction, including PBP2a, to further promote cell virulence and antibiotic resistance . Therefore, blocking STX biosynthesis pathways has become an innovative therapeutic approach.…”

“…Therefore, blocking STX biosynthesis pathways has become an innovative therapeutic approach. Thus far, cholesterol‐lowering drugs, including compound BPH‐652 and statins, have shown capability of inhibiting S. aureus virulence by targeting the enzymatic activity, for example, dehydrosqualene synthase (CrtM), along the pathway for STX biosynthesis . However, these drugs suffer from off‐target issues, as human and S. aureus share the same pathway for biosynthesis of presqualene diphosphate, an intermediate used to produce downstream cholesterol or STX.…”

Are We There Yet? How and When Specific Biotechnologies Will Improve Human Health

“…CRISPR/Cas9 technology can also be instrumental to selectively kill pathogens (or eliminate their antibiotic plasmids) by spreading bacterial or viral vigilantes that target the corresponding resistance genes in the microbiome . It is also possible to re‐sensitize specific microorganisms by making them amenable to the action of existing antibiotics through co‐treatment with other drugs . Ultimately, the success of antimicrobial strategies may depend on a deeper understanding of the molecular ecology of the microbiome, its interplay with environmental factors (including our immune system) and the effect of other medicaments in our own physiology…”

Photo-Disassembly of Membrane Microdomains Revives Conventional Antibiotics against MRSA

“…This pigment is expressed for S. aureus pathogenesis and used as an antioxidant to neutralize reactive oxygen species (ROS) produced by the host immune system (12). Recent studies on cell membrane organization further suggest that STX and its derivatives condense as the constituent lipids of functional membrane microdomains (FMM), endowing membrane integrity and providing a platform to facilitate protein-protein oligomerization and interaction, including PBP2a, to further promote cell virulence and antibiotic resistance (13). Therefore, blocking STX biosynthesis pathways has become an innovative therapeutic approach.…”