Molecular Mechanisms Related to Colistin Resistance against Gram Negative Isolates

Abstract

Polymyxins, a structurally distinct class of non-ribosomal, cyclic oligopeptides antimicrobials, include five chemically distinguished compounds (polymyxins A, B, C, D, and E) of which polymyxin B and colistin (polymyxin E) are the only two polymyxins currently available on the market. In 1947 in Japan, Koyama discovered polymyxins, initially, he had reported the colistin as a secondary metabolite of the Gram-positive soil bacterium Paenibacillus polymyxa subsp. Colistinus. Colistin is an active agent against aerobic Gram-negative pathogens that frequently represent the mainspring of life-threatening infections, such as carbapenem-resistant P. aeruginosa, A. baumannii, K. pneumoniae, E. coli, and other Enterobacterales. Noteworthy, some bacterial species, such as; Serratia marcescens, Proteus spp., Providencia spp., Morganella morganii, Vibrio cholera, Brucella, Campylobacter, Legionella, Chromobacterium, Neisseria spp., Edwardsiella , some Aeromonas species, Burkholderia cepacia, anaerobic Gram-negative cocci, eukaryotic microbes, and mammalian cells, are possessing intrinsic colistin resistance. Antibacterial activity of colistin occurs on the outer membrane (OM) of Gram-negative bacteria. The antibacterial activity of colistin occurs through two-step mechanisms that are initial binding and employed permeabilization of the outer LPS membrane induces the displacement of Ca²⁺ and Mg²⁺ ions from the phosphate groups of LPS in a competitive way resulting in destabilizing cytoplasmic membrane, leading to disruption of the outer LPS and the loss of inner cellular contents, hence bacterial killing. The critical step of colistin action is based on the electrostatic interaction of cationic colistin peptide and anionic lipid A membrane also known as endotoxin component of LPS layer.