Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in <italic toggle="yes">Enterobacteriaceae</italic>: 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 carbap...

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Autores principales:	Masego Mmatli, Nontombi Marylucy Mbelle, Nontuthuko E. Maningi, John Osei Sekyere
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	carbapenem resistance polymyxin resistance Enterobacteriaceae transcription factors resistance mechanisms Enterobacteriales Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b61de0180a614e88bf0e4b2ce9efd604
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spelling	oai:doaj.org-article:b61de0180a614e88bf0e4b2ce9efd6042021-12-02T19:46:19ZEmerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in <italic toggle="yes">Enterobacteriaceae</italic>: a Systematic Review of Current Reports10.1128/mSystems.00783-202379-5077https://doaj.org/article/b61de0180a614e88bf0e4b2ce9efd6042020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00783-20https://doaj.org/toc/2379-5077ABSTRACT 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.Masego MmatliNontombi Marylucy MbelleNontuthuko E. ManingiJohn Osei SekyereAmerican Society for Microbiologyarticlecarbapenem resistancepolymyxin resistanceEnterobacteriaceaetranscription factorsresistance mechanismsEnterobacterialesMicrobiologyQR1-502ENmSystems, Vol 5, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	carbapenem resistance polymyxin resistance Enterobacteriaceae transcription factors resistance mechanisms Enterobacteriales Microbiology QR1-502
spellingShingle	carbapenem resistance polymyxin resistance Enterobacteriaceae transcription factors resistance mechanisms Enterobacteriales Microbiology QR1-502 Masego Mmatli Nontombi Marylucy Mbelle Nontuthuko E. Maningi John Osei Sekyere Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in <italic toggle="yes">Enterobacteriaceae</italic>: a Systematic Review of Current Reports
description	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.
format	article
author	Masego Mmatli Nontombi Marylucy Mbelle Nontuthuko E. Maningi John Osei Sekyere
author_facet	Masego Mmatli Nontombi Marylucy Mbelle Nontuthuko E. Maningi John Osei Sekyere
author_sort	Masego Mmatli
title	Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in <italic toggle="yes">Enterobacteriaceae</italic>: a Systematic Review of Current Reports
title_short	Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in <italic toggle="yes">Enterobacteriaceae</italic>: a Systematic Review of Current Reports
title_full	Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in <italic toggle="yes">Enterobacteriaceae</italic>: a Systematic Review of Current Reports
title_fullStr	Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in <italic toggle="yes">Enterobacteriaceae</italic>: a Systematic Review of Current Reports
title_full_unstemmed	Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in <italic toggle="yes">Enterobacteriaceae</italic>: a Systematic Review of Current Reports
title_sort	emerging transcriptional and genomic mechanisms mediating carbapenem and polymyxin resistance in <italic toggle="yes">enterobacteriaceae</italic>: a systematic review of current reports
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/b61de0180a614e88bf0e4b2ce9efd604
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Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in <italic toggle="yes">Enterobacteriaceae</italic>: a Systematic Review of Current Reports

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