Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in Enterobacteriaceae: a Systematic Review of Current Reports

Abstract

The spread of carbapenem- and polymyxin-resistant Enterobacteriaceae poses a significant threat to public health, challenging clinicians worldwide with limited therapeutic options. This review describes the current coding and noncoding genetic and transcriptional mechanisms mediating carbapenem and polymyxin resistance, respectively. A systematic review of all studies published in PubMed database between 2015 to October 2020 was performed. Journal articles evaluating carbapenem and polymyxin resistance mechanisms, respectively, were included. The search identified 171 journal articles for inclusion. Different New Delhi metallo-β-lactamase (NDM) carbapenemase variants had different transcriptional and affinity responses to different carbapenems. Mutations within the Klebsiella pneumoniae carbapenemase (KPC) mobile transposon, Tn4401, affect its promoter activity and expression levels, increasing carbapenem resistance. Insertion of IS26 in ardK increased imipenemase expression 53-fold. ompCF porin downregulation (mediated by envZ and ompR mutations), micCF small RNA hyperexpression, efflux upregulation (mediated by acrA, acrR, araC, marA, soxS, ramA, etc.), and mutations in acrAB-tolC mediated clinical carbapenem resistance when coupled with β-lactamase activity in a species-specific manner but not when acting without β-lactamases. Mutations in pmrAB, phoPQ, crrAB, and mgrB affect phosphorylation of lipid A of the lipopolysaccharide through the pmrHFIJKLM (arnBCDATEF or pbgP) cluster, leading to polymyxin resistance; mgrB inactivation also affected capsule structure. Mobile and induced mcr, efflux hyperexpression and porin downregulation, and Ecr transmembrane protein also conferred polymyxin resistance and heteroresistance. Carbapenem and polymyxin resistance is thus mediated by a diverse range of genetic and transcriptional mechanisms that are easily activated in an inducing environment. The molecular understanding of these emerging mechanisms can aid in developing new therapeutics for multidrug-resistant Enterobacteriaceae isolates.

Keywords: Enterobacteriaceae; Enterobacteriales; antimicrobial resistance mechanisms; carbapenem resistance; carbapenems; colistin; polymyxin resistance; resistance mechanisms; transcription factors.

FIG 1

Summary of the carbapenem resistance mechanisms seen in Gram-negative bacteria (Enterobacteriaceae). (A) High-level resistance to carbapenems can be mediated by the alteration of membrane permeability due to porin mutations, restricting the entry of antibiotics into the periplasmic space. (B and C) Further, the hydrolysis of carbapenems (green balls) by highly expressed (increased concentrations of) AmpCs, and extended-spectrum β-lactamases (ESBLs) (B), as well as carbapenemases (C), respectively, also confer resistance to carbapenems. (D) Increased efflux pump activity also decreases the concentration of antibiotics (carbapenems) in the periplasmic space, reducing susceptibility to the antibiotic. (E) Finally, mobile genetic elements (MGEs), such as plasmids (with high copy numbers), transposons, and insertion sequences (upstream or within promoter sequences), can increase the expression levels of carbapenemases, AmpCs, and ESBLs, leading to higher levels of resistance to carbapenems. The figure was constructed using chemix.org and Paint 3D.

FIG 2

Representation of the various mechanisms and determinants interacting to mediate polymyxin resistance in Gram-negative bacteria. The LPS of the outer membrane of Gram-negative bacteria is modified through PmrC, the pbgP operon, and mcr-type genes. The PmrC and PbgP genes are regulated by three two-component systems—PhoPQ, PmrAB, and CrrAB—that are interconnected by CrrC and PmrD proteins. The newly discovered DedA and Ecr proteins also activate PbgP through PhoPQ, whereas Ecr also activates DedA and TolC. Heteroresistance in Enterobacter sp. is thought to be mediated by Ecr membrane proteins. A “+” indicates activation toward upregulation; a “–” indicates repression/inhibition toward downregulation. The diagram was constructed using Paint 3D with a structure based on one by Cheng et al. (75).