Molecular mechanisms of polymyxin resistance and detection of mcr genes

Abstract

Antibiotic resistance is an ever-increasing global problem. Major commercial antibiotics often fail to fight common bacteria, and some pathogens have become multi-resistant. Polymyxins are potent bactericidal antibiotics against gram-negative bacteria. Known resistance to polymyxin includes intrinsic, mutational and adaptive mechanisms, with the recently described horizontally acquired resistance mechanisms. In this review, we present several strategies for bacteria to develop enhanced resistance to polymyxins, focusing on changes in the outer membrane, efflux and other resistance determinants. Better understanding of the genes involved in polymyxin resistance may pave the way for the development of new and effective antimicrobial agents. We also report novel in silico tested primers for PCR assay that may be able distinguish colistin-resistant isolates carrying the plasmid-encoded mcr genes and will assist in combating the spread of colistin resistance in bacteria.

Colistin and its role in the Era of antibiotic resistance: an extended review (2000–2019)

“…Generally, polymyxins display reduced activity against Gram-positive bacteria as they do not attach favourably to lipoteichoic acid found in the cytoplasmic membrane. However, as previously mentioned, polymyxin B has been found to have a broad spectrum of activity, mostly against GNB, but has also been shown to be effective against Gram-positive bacteria [17,18].…”

“…Other modifications related to chromosomally polymyxin resistance have been reported, such as the decrease in the number of acyl moieties via lpxR-like deacylation and hydroxylation of lipid A [58]. Besides, acylation of lipid A, these modifications are capable of changing the permeability barrier properties of the OM [18].…”

“…Another polymyxin resistance mechanism in K. pneumoniae is the overproduction of the surface anionic capsular polysaccharides (CPS) [23] that represent a protective barrier against polymyxins, where the upregulation of capsular biosynthesis genes, namely; siaD, OmpA, and cps operon (wca), hinders the binding of polymyxins with lipid A [18] by trapping polymyxins [40]. Fresno et al [41] reported that the association between the surface CPS and the LPS is mediated through an ionic interaction that is stabilized by divalent cations.…”

“…Regarding polymyxin B, although it exhibits a broad spectrum of activity, mostly against GNB, it has also been shown to be effective against Gram-positive bacteria such as; Staphylococcus aureus [17], Streptococcus gordonii, Streptococcus agalactiae [18], as well as against facultative anaerobic bacteria such as Listeria monocytogenes [19].…”

“…Unfortunately, the overuse and misuse of colistin among humans and animals medicine have led to the global emergence of colistin-resistant pathogens. However, the development of bacteria resistant against colistin may also occur unaccompanied by any prior exposure to colistin, leaving clinicians barehanded to treat patients [18]. Indeed, the polymyxins now play a critical role mainly against life-threatening Gramnegative infections, as they are one of the few, and on occasion, the sole antimicrobial agent, retaining activity against MDR GNB [13].…”