Abstract
One of the major families of membrane proteins found in prokaryote genome corresponds to the transporters. Among them, the resistance-nodulation-cell division (RND) transporters are highly studied, as being responsible for one of the most problematic mechanisms used by bacteria to resist to antibiotics, i.e., the active efflux of drugs. In Gram-negative bacteria, these proteins are inserted in the inner membrane and form a tripartite assembly with an outer membrane factor and a periplasmic linker in order to cross the two membranes to expulse molecules outside of the cell. A lot of information has been collected to understand the functional mechanism of these pumps, especially with AcrAB-TolC from Escherichia coli, but one missing piece from all the suggested models is the role of peptidoglycan in the assembly. Here, by pull-down experiments with purified peptidoglycans, we precise the MexAB-OprM interaction with the peptidoglycan from Escherichia coli and Pseudomonas aeruginosa, highlighting a role of the peptidoglycan in stabilizing the MexA-OprM complex and also differences between the two Gram-negative bacteria peptidoglycans.
Highlights
The cell wall of Gram-negative bacteria comprises three main layers: the outer membrane lipid bilayer coated by lipopolysaccharides at the exterior; the inner membrane that meets the cytoplasm; and in between the periplasmic matrix where peptidoglycan (PG)confers the mechanical rigidity of the cell wall
We recently solved the structure of the whole MexAB-OprM pump from P. aeruginosa by cryo-electron microscopy (cryo-EM) [16] showing a structure of around 230 Å long between the two membranous domains, which is compatible with the size of the periplasm estimated by cryo-transmission electron microscopy (Cryo-TEM) [36]
E. coli and P. aeruginosa showing some differences between the two bacteria
Summary
Confers the mechanical rigidity of the cell wall Membrane transporters such as efflux pumps span these layers and expulse a wide variety of drugs leading to natural and acquired antimicrobial resistances. MexAB-OprM from Pseudomonas aeruginosa (P. aeruginosa), an opportunistic Gram-negative bacterium responsible of severe nosocomial infections and having developed resistance to several families of antibiotics. It has been recently classified as high priority by WHO in antimicrobial research [3] and belongs to the group ESKAPE named by the initials of the pathogens for which there is an urgent need for new treatments. The structure of each protein forming the pump has been solved by X-ray crystallography [4,5,6,7,8,9,10,11,12] and the whole assembly was recently determined by cryo-electron microscopy (cryo-EM) [13,14,15,16]
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