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Architecture of bacterial lipid rafts; inhibition of virulence and antibiotic resistance using raft-disassembling small molecules

Final Report Summary - BACRAFTS (Architecture of bacterial lipid rafts; inhibition of virulence and antibiotic resistance using raft-disassembling small molecules)

A number of bacterial cell processes are confined in platforms termed functional membrane microdomains (FMM), some of whose organizational and functional features resemble those of lipid rafts of eukaryotic cells. How bacteria organize these intricate platforms and their biological significance remains an important question. In this project, we used the the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) to demonstrate how bacteria organise FMM. Membrane carotenoid interacts with the scaffold protein flotillin for the formation of FMM. We were able to visualise this process using super-resolution array tomography. These membrane platforms accumulate multimeric protein complexes, for which flotillin facilitates efficient oligomerization. We identified several protein complexes for which FMM localisationis central for their correct functionality. One of these proteins is PBP2a, responsible for penicillin resistance in MRSA. Flotillin mutants are unable to oligomerize PBP2a efficiently and therefore, the activity of PBP2a is compromised in this strain. 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 susceptible to a conventional penicillin treatment. Overall, our study demonstrates the existence of sophisticated cell organization programs in bacteria and defines alternative antimicrobial therapies to fight antibiotic-resistant pathogens using conventional antibiotics.