Oral statins appear to help the host in combating antibiotic-resistant bacteria

Cell integrity depends on the precise organization of its limiting cell membranes, whose molecular organization we understand poorly. The established dogma about the fluid mosaic model had suggested that membrane proteins and lipids diffuse freely and therefore are homogenously distributed. However, recent advances show that membranes contain various lipid species that segregate laterally into discrete microdomains. One of the most interesting examples in membrane organization is the formation of “lipid rafts” in eukaryotic cells (i.e. cells having chromosome pairs in their nuclei). Eukaryotic cells organize those proteins that are involved in signal transduction and membrane trafficking into cholesterol- and sphingolipid-enriched membrane microdomains, which have been termed lipid rafts. Raft integrity requires activity of the raft-associated scaffold protein flotillin, which recruits proteins to rafts to facilitate their interaction and oligomerization. How cells organize lipid rafts remains poorly understood. Biochemical evidence nonetheless suggests that lipid rafts serve as platforms to control protein-protein interactions and to promote more efficient triggering of signal-transduction cellular processes.

A number of bacterial cell processes are confined functional membrane microdomains (FMMs) –– that appear to be structurally and functionally similar to lipid rafts of eukaryotic cells. But –– hHow do bacteria organize these intricate platforms, and what is their biological significance? Using the pathogenic methicillin-resistant

Staphylococcus aureus (MRSA), authors [see attached article] demonstrated that membrane-carotenoid interactions with the scaffold protein flotillin leads to FMM formation, which can then be visualized using super-resolution array tomography. These membrane platforms accumulate chains of protein complexes, for which flotillin facilitates efficient oligomerization (i.e. the hooking-up of these chains). One of these bacterial proteins is PBP2a, responsible for penicillin resistance in the phenomenon MRSA, which can lead to infections that are serious to patients. Authors show that flotillin mutants are defective in PBP2a oligomerization.

Perturbation of FMM assembly –– using available drugs, such as the cholesterol-lowering statins –– interferes with PBP2a oligomerization and disables MRSA penicillin resistance in culture and in the intact animal host (mouse or human), resulting in MRSA infections that are (successfully) susceptible to penicillin treatment. This breakthrough study establishes that bacteria possess sophisticated cell organization programs and defines alternative therapies to fight multidrug-resistant pathogens, using conventional antibiotics.

Cell Dec 2o17; 171: 1–14

This entry was posted in Center for Environmental Genetics. Bookmark the permalink.