Abstract
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.
Highlights
EMERGENCE OF RESISTANCEThe antibiotics have been widely used in human, animal husbandry, and aquaculture, aiming to fight bacterial infections
Reviewed by: Swaminath Srinivas, University of Illinois at Urbana-Champaign, United States Gerald Larrouy-Maumus, Imperial College London, United Kingdom
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
Summary
The antibiotics have been widely used in human, animal husbandry, and aquaculture, aiming to fight bacterial infections. A steady increase in antibiotic resistance coupled with the decline in the development of new drugs is leading the world toward the pre–antibiotic era [4]. This global public health threat requires immediate multidisciplinary steps to achieve the sustainable development goals, which are a collection of 17 interlinked global goals designed to be a roadmap for achieving a better and more sustainable future for all. Failure of carbapenems against Gram-negative bacteria has led to the unprecedented increase in the use of colistin (one of the last-resort drugs) and subsequent emergence and dissemination of colistin resistance [14]. We present an overview of recognition of alternative mechanisms of colistin action, the spread of acquired colistin resistance determinants, and diverse strategies taken by bacteria to extend resistance against colistin antibiotic
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