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.
Highlights
The spread of carbapenem- and polymyxin-resistant Enterobacteriaceae poses a significant threat to public health, challenging clinicians worldwide with limited therapeutic options
Carbapenem-resistant Enterobacteriaceae are designated by the World Health Organization (WHO) as critical priority pathogens due to their multidrug resistance (MDR) phenotypes and associated morbidities and mortalities [5]
In K. pneumoniae, Salmonella enterica serotype Typhimurium, and other Enterobacteriaceae species, including Enterobacter cloacae complex (E. asburiae and E. cloacae) and Raoultella ornithinolytica, porin deficiency reduces the susceptibility of isolates to carbapenem but does not confer clinical resistance, and b-lactamase activity is required [56, 57]
Summary
Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in Enterobacteriaceae: a Systematic Review of Current Reports. Masego Mmatli,a Nontombi Marylucy Mbelle,a Nontuthuko E. Maningi,a,b John Osei Sekyerea aDepartment of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa bDepartment of Microbiology, School of Life Sciences, University of KwaZulu-Natal, Durban, South Africa
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