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The resulting disruption of the inner membrane is proposed as the main cause of cell death. After destabilizing the outer membrane, colistin binds to LPS molecules that are located in the outer leaflet of the cytoplasmic membrane while they await transport to the outer membrane. coli through electrostatic interactions with negatively charged phosphate groups on the lipid A moiety of LPS. coli.Ĭolistin initially targets LPS in the outer membrane of E. Colistin susceptibility and resistance in E. The findings from Knopp and colleagues thus further expand our view on the potential for the evolution of novel auxiliary regulators of bacterial two-component regulatory systems.įig 1. Auxiliary peptides that directly interact with sensor histidine kinases appear to be common and most appear to suppress the activity of its cognate histidine kinase, but peptide activators, like the small (65 amino acids) transmembrane protein SafA, which interacts directly with the sensor histidine kinase PhoQ to activate the PhoPQ system, have also been described in E. The authors provide evidence that their peptides directly interact with the sensor protein kinase PmrB, thus leading to constitutive activation of the regulatory system and increased expression of EptA, ArnT, and other genes that are controlled by the response regulator PmrA. Importantly, all peptides act as activators of the PmrAB (BasRS) two-component system, leading to the up-regulated production of enzymes that catalyze modifications of lipid A by 4-amino-4-deoxy-L-arabinose (by ArnT) and phosphoethanolamine (by EptA) ( Fig 1). A total of 6 peptides, without any sequence homology to each other or to other proteins in public databases, were found to confer resistance to colistin to E. The clone libraries were then screened to identify peptides that conferred resistance to colistin. coli clones that expressed more than 500 million random peptides of 10 to 50 amino acids in length. The authors of this study generated a library of E. In this issue of PLOS Genetics, Knopp and colleagues describe an entirely novel mechanism by which E. coli) appear to be one of the most prominent causes for colistin resistance in clinical isolates of E. Mutations in the two-component regulatory system PmrAB (also termed BasRS in E. These changes can be mediated by the acquisition of mobilized colistin resistance ( mcr) genes, of which 10 homologues have so far been described, or the accumulation of mutations that lead to an increased expression of chromosomal genes that mediate lipid A modifications. While a variety of resistance mechanisms have been described, the most commonly encountered are those that lead to modifications of the lipid A moiety that reduce the affinity of colistin to lipid A or inhibit its successful insertion into the outer membrane ( Fig 1). The increasing importance of colistin has drawn attention to mechanisms of acquired colistin resistance in important multidrug-resistant opportunistic pathogens, like Escherichia coli and Klebsiella pneumoniae. īecause of the rapid increase in infections caused by multidrug-resistant strains of the family Enterobacteriaceae, colistin is now increasingly used as an antibiotic of last resort, and its use is increasing globally. Indeed, the bactericidal activity of colistin appears to be primarily mediated by the permeabilization of the inner membrane through interactions between colistin and the LPS molecules that are located in the outer leaflet of the inner membrane after synthesis in the cytoplasm. However, destabilization of the outer membrane by colistin may not be lethal to the bacterial cell. Colistin then inserts itself into the outer membrane, negatively affecting the integrity of this barrier. Colistin first acts by replacing Ca 2+ and Mg 2+ cations that stabilize the outer membrane through electrostatic interactions with the anionic phosphate groups of the lipid A moiety of LPS. The antibiotic colistin (polymyxin E) is an amphipathic, non-ribosomally synthesized, cyclic lipopeptide, which is selectively bactericidal for gram-negative aerobic bacilli, as it targets lipopolysaccharide (LPS) molecules in their outer membranes.