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Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae

Extensively drug-resistant Klebsiella pneumoniae (XDR-KP) infections cause high mortality and are disseminating globally. Identifying the genetic basis underpinning resistance allows for rapid diagnosis and treatment. XDR isolates sourced from Greece and Brazil, including 19 polymyxin-resistant and...

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Autores principales: Pitt, Miranda E., Elliott, Alysha G., Cao, Minh Duc, Ganesamoorthy, Devika, Karaiskos, Ilias, Giamarellou, Helen, Abboud, Cely S., Blaskovich, Mark A. T., Cooper, Matthew A., Coin, Lachlan J. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Microbiology Society 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885010/
https://www.ncbi.nlm.nih.gov/pubmed/29431605
http://dx.doi.org/10.1099/mgen.0.000158
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author Pitt, Miranda E.
Elliott, Alysha G.
Cao, Minh Duc
Ganesamoorthy, Devika
Karaiskos, Ilias
Giamarellou, Helen
Abboud, Cely S.
Blaskovich, Mark A. T.
Cooper, Matthew A.
Coin, Lachlan J. M.
author_facet Pitt, Miranda E.
Elliott, Alysha G.
Cao, Minh Duc
Ganesamoorthy, Devika
Karaiskos, Ilias
Giamarellou, Helen
Abboud, Cely S.
Blaskovich, Mark A. T.
Cooper, Matthew A.
Coin, Lachlan J. M.
author_sort Pitt, Miranda E.
collection PubMed
description Extensively drug-resistant Klebsiella pneumoniae (XDR-KP) infections cause high mortality and are disseminating globally. Identifying the genetic basis underpinning resistance allows for rapid diagnosis and treatment. XDR isolates sourced from Greece and Brazil, including 19 polymyxin-resistant and five polymyxin-susceptible strains, were subjected to whole genome sequencing. Seventeen of the 19 polymyxin-resistant isolates harboured variations upstream or within mgrB. The most common mutation identified was an insertion at nucleotide position 75 in mgrB via an ISKpn26-like element in the ST258 lineage and ISKpn13 in one ST11 isolate. Three strains acquired an IS1 element upstream of mgrB and another strain had an ISKpn25 insertion at 133 bp. Other isolates had truncations (C28STOP, Q30STOP) or a missense mutation (D29E) affecting mgrB. Complementation assays revealed all mgrB perturbations contributed to resistance. Missense mutations in phoQ (T281M, G385C) were also found to facilitate resistance. Several variants in phoPQ co-segregating with the ISKpn26-like insertion were identified as potential partial suppressor mutations. Three ST258 samples were found to contain subpopulations with different resistance-conferring mutations, including the ISKpn26-like insertion colonizing with a novel mutation in pmrB (P158R), both confirmed via complementation assays. These findings highlight the broad spectrum of chromosomal modifications which can facilitate and regulate resistance against polymyxins in K. pneumoniae.
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spelling pubmed-58850102018-04-05 Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae Pitt, Miranda E. Elliott, Alysha G. Cao, Minh Duc Ganesamoorthy, Devika Karaiskos, Ilias Giamarellou, Helen Abboud, Cely S. Blaskovich, Mark A. T. Cooper, Matthew A. Coin, Lachlan J. M. Microb Genom Research Article Extensively drug-resistant Klebsiella pneumoniae (XDR-KP) infections cause high mortality and are disseminating globally. Identifying the genetic basis underpinning resistance allows for rapid diagnosis and treatment. XDR isolates sourced from Greece and Brazil, including 19 polymyxin-resistant and five polymyxin-susceptible strains, were subjected to whole genome sequencing. Seventeen of the 19 polymyxin-resistant isolates harboured variations upstream or within mgrB. The most common mutation identified was an insertion at nucleotide position 75 in mgrB via an ISKpn26-like element in the ST258 lineage and ISKpn13 in one ST11 isolate. Three strains acquired an IS1 element upstream of mgrB and another strain had an ISKpn25 insertion at 133 bp. Other isolates had truncations (C28STOP, Q30STOP) or a missense mutation (D29E) affecting mgrB. Complementation assays revealed all mgrB perturbations contributed to resistance. Missense mutations in phoQ (T281M, G385C) were also found to facilitate resistance. Several variants in phoPQ co-segregating with the ISKpn26-like insertion were identified as potential partial suppressor mutations. Three ST258 samples were found to contain subpopulations with different resistance-conferring mutations, including the ISKpn26-like insertion colonizing with a novel mutation in pmrB (P158R), both confirmed via complementation assays. These findings highlight the broad spectrum of chromosomal modifications which can facilitate and regulate resistance against polymyxins in K. pneumoniae. Microbiology Society 2018-02-12 /pmc/articles/PMC5885010/ /pubmed/29431605 http://dx.doi.org/10.1099/mgen.0.000158 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Pitt, Miranda E.
Elliott, Alysha G.
Cao, Minh Duc
Ganesamoorthy, Devika
Karaiskos, Ilias
Giamarellou, Helen
Abboud, Cely S.
Blaskovich, Mark A. T.
Cooper, Matthew A.
Coin, Lachlan J. M.
Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae
title Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae
title_full Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae
title_fullStr Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae
title_full_unstemmed Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae
title_short Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae
title_sort multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant klebsiella pneumoniae
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885010/
https://www.ncbi.nlm.nih.gov/pubmed/29431605
http://dx.doi.org/10.1099/mgen.0.000158
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