History of mankind is regarded as struggle against infectious diseases. Rather than observing the withering away of bacterial diseases, antibiotic resistance has emerged as a serious global health concern. Medium of antibiotic resistance in bacteria varies greatly and comprises of target protection, target substitution, antibiotic detoxification and block of intracellular antibiotic accumulation. Further aggravation to prevailing situation arose on observing bacteria gradually becoming resistant to different classes of antibiotics through acquisition of resistance genes from same and different genera of bacteria. Attributing bacteria with feature of better adaptability, dispersal of antibiotic resistance genes to minimize effects of antibiotics by various means including horizontal gene transfer (conjugation, transformation, and transduction), Mobile genetic elements (plasmids, transposons, insertion sequences, integrons, and integrative-conjugative elements) and bacterial toxin-antitoxin system led to speedy bloom of antibiotic resistance amongst bacteria. Proficiency of bacteria to obtain resistance genes generated an unpleasant situation; a grave, but a lot unacknowledged, feature of resistance gene transfer.
Colistin regained global interest as a consequence of the rising prevalence of multidrug-resistant Gram-negative Enterobacteriaceae. In parallel, colistin-resistant bacteria emerged in response to the unregulated use of this antibiotic. However, some Gram-negative species are intrinsically resistant to colistin activity, such as Neisseria meningitides, Burkholderia species, and Proteus mirabilis. Most identified colistin resistance usually involves modulation of lipid A that decreases or removes early charge-based interaction with colistin through up-regulation of multistep capsular polysaccharide expression. The membrane modifications occur by the addition of cationic phosphoethanolamine (pEtN) or 4-amino-l-arabinose on lipid A that results in decrease in the negative charge on the bacterial surface. Therefore, electrostatic interaction between polycationic colistin and lipopolysaccharide (LPS) is halted. It has been reported that these modifications on the bacterial surface occur due to overexpression of chromosomally mediated two-component system genes (PmrAB and PhoPQ) and mutation in lipid A biosynthesis genes that result in loss of the ability to produce lipid A and consequently LPS chain, thereafter recently identified variants of plasmid-borne genes (mcr-1 to mcr-10). It was hypothesized that mcr genes derived from intrinsically resistant environmental bacteria that carried chromosomal pmrC gene, a part of the pmrCAB operon, code three proteins viz. pEtN response regulator PmrA, sensor kinase protein PmrAB, and phosphotransferase PmrC. These plasmid-borne mcr genes become a serious concern as they assist in the dissemination of colistin resistance to other pathogenic bacteria. This review presents the progress of multiple strategies of colistin resistance mechanisms in bacteria, mainly focusing on surface changes of the outer membrane LPS structure and other resistance genetic determinants. New handier and versatile methods have been discussed for rapid detection of colistin resistance determinants and the latest approaches to revert colistin resistance that include the use of new drugs, drug combinations and inhibitors. Indeed, more investigations are required to identify the exact role of different colistin resistance determinants that will aid in developing new less toxic and potent drugs to treat bacterial infections. Therefore, colistin resistance should be considered a severe medical issue requiring multisectoral research with proper surveillance and suitable monitoring systems to report the dissemination rate of these resistant genes.
Colistin, a polycationic antimicrobial peptide, is one of the last-resort antibiotics for treating infections caused by carbapenem-resistant Gram-negative bacteria. The antibacterial activity of colistin occurs through electrostatic interaction between the polycationic peptide group of colistin and the negatively charged phosphate groups of lipid A membrane. This study investigated the interaction of colistin with the outer membrane and surface constituents of resistant and susceptible strains of Escherichia coli and Aeromonas veronii harboring mcr-1 resistance gene. Bacterial membrane and lipopolysaccharide used in this study were isolated from susceptible as well as colistin-resistant strains of E. coli and A. veronii. Interaction of colistin with the bacterial surface was studied by deoxycholate and lysozyme sensitivity test, N-phenyl-1-naphthylamine (NPN) uptake assay, Atomic force microscopy (AFM), Zeta potential measurements and 1H NMR. The binding affinity of colistin was found to be lower with outer membrane from resistant strains in comparison with the susceptible strains. Colistin exposure enhances the outer membrane permeability of the susceptible strains to deoxycholate and lysozyme. However, on the other hand, colistin dose of 256 µg/mL did not permeabilize the outer membrane of resistant bacteria. The NPN permeability in resistant strains was greater in comparison with susceptible strains. Atomic force microscopy images depicted smooth, featherless and deformed membranes in treated susceptible cells. Contrary to the above, resistant treated cells displayed surface roughness topography even at 256 µg/mL colistin concentration. Surface charge alterations were confirmed by Zeta potential measurements as a function of the growth phase. Mid-logarithmic phase susceptible strains showed a greater negative charge than resistant strains upon exposure to colistin. However, there was no statistical variation in the Zeta potential measurements between resistant and susceptible strains at the stationary phase. NMR analysis revealed line broadening in susceptible strains with increasing colistin: LPS aggregates mass ratio. Moreover, resistant strains did not show line broadening for the outer membrane, even at the highest mass ratio. The findings of this study suggest that the resistant strains of E. coli and A. veronii can block the electrostatic contact between the cationic peptide and anionic lipid A component that drives the first phase of colistin action, thereby preventing hydrophobically driven second-tier action of colistin on the outer lipopolysaccharide layer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.