Emerging transcriptional and genomic mechanisms mediating carbapenem and polymyxin resistance in Enterobacteriaceae : a systematic review of current reports

dc.contributor.authorMmatli, Masego
dc.contributor.authorMbelle, Nontombi Marylucy
dc.contributor.authorManingi, Nontuthuko Excellent
dc.contributor.authorOsei Sekyere, John
dc.date.accessioned2021-04-07T09:46:07Z
dc.date.available2021-04-07T09:46:07Z
dc.date.issued2020-11
dc.descriptionSupplementary material : Figure S1. Flow chart showing the literature search strategy, inclusion and exclusion criteria, and the final number of manuscripts used for the review.en_ZA
dc.description.abstractThe 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.en_ZA
dc.description.departmentMedical Microbiologyen_ZA
dc.description.librarianhj2021en_ZA
dc.description.urihttps://msystems.asm.orgen_ZA
dc.identifier.citationMmatli M, Mbelle NM, Maningi NE,Osei Sekyere J. 2020. Emerging transcriptional and genomic mechanisms mediating carbapenem and polymyxin resistance in Enterobacteriaceae: a systematic review of current reports. mSystems 5:e00783-20.https://doi.org/10.1128/mSystems.00783-20.en_ZA
dc.identifier.issn2379-5077 (online)
dc.identifier.other10.1128/mSystems.00783-20
dc.identifier.urihttp://hdl.handle.net/2263/79336
dc.language.isoenen_ZA
dc.publisherAmerican Society for Microbiologyen_ZA
dc.rights© 2020 Mmatli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.en_ZA
dc.subjectCarbapenem resistanceen_ZA
dc.subjectPolymyxin resistanceen_ZA
dc.subjectEnterobacteriaceaeen_ZA
dc.subjectTranscription factorsen_ZA
dc.subjectResistance mechanismsen_ZA
dc.subjectEnterobacterialesen_ZA
dc.subjectAntimicrobial resistance mechanismsen_ZA
dc.subjectColistinen_ZA
dc.subjectCarbapenemsen_ZA
dc.subjectKlebsiella pneumoniae carbapenemase (KPC)en_ZA
dc.subjectNew Delhi metallo-β-lactamase (NDM)en_ZA
dc.titleEmerging transcriptional and genomic mechanisms mediating carbapenem and polymyxin resistance in Enterobacteriaceae : a systematic review of current reportsen_ZA
dc.typeArticleen_ZA

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