Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment

Yan Zhu, Irene Galani, Ilias Karaiskos, Jing Lu, Su Mon Aye, Jiayuan Huang, Heidi H. Yu, Tony Velkov, Helen Giamarellou, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objectives: Polymyxins (i.e., polymyxin B and colistin) are used as a last-line therapy to combat multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance in K. pneumoniae is increasingly reported worldwide. This study identified the genetic variations responsible for high-level colistin resistance in MDR K. pneumoniae clinical isolates. Methods: Sixteen MDR K. pneumoniae isolates were obtained from stool samples of 8 patients before and after colistin treatment. Their genomes were sequenced on Illumina MiSeq to determine genetic variations. Results: Fifteen of 16 isolates harboured ISKpn26-like element insertion at nucleotide position 75 of mgrB, abolishing its negative regulation on phoPQ; while colistin-susceptible ATH7 contained intact mgrB and phoQ. Interestingly, each of the 7 mgrB-disrupted, colistin-susceptible isolates contained a nonsynonymous substitution in PhoQ (G39S, L239P, N253T or V446G), potentially impairing its function and intergenically suppressing the effect caused by mgrB inactivation. Additionally, three of the 7 corresponding mgrB-disrupted, colistin-resistant isolates harboured a secondary nonsynonymous substitution in PhoQ (N253P, D438H or T439P). Conclusions: This is the first report of phoQ mutations in mgrB-disrupted, colistin-susceptible K. pneumoniae clinical isolates. We also discovered multiple phoQ mutations in mgrB-disrupted, colistin-resistant strains. Our findings highlight the multifaceted molecular mechanisms of colistin resistance in K. pneumoniae.

Original languageEnglish
Pages (from-to)312-321
Number of pages10
JournalJournal of Infection
Volume79
Issue number4
DOIs
Publication statusPublished - 1 Oct 2019

Keywords

  • Colistin
  • Genomics
  • Klebsiella pneumoniae
  • mgrB
  • phoQ

Cite this

Zhu, Yan ; Galani, Irene ; Karaiskos, Ilias ; Lu, Jing ; Aye, Su Mon ; Huang, Jiayuan ; Yu, Heidi H. ; Velkov, Tony ; Giamarellou, Helen ; Li, Jian. / Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment. In: Journal of Infection. 2019 ; Vol. 79, No. 4. pp. 312-321.
@article{c003db6d97514399bd5be16346ba59ab,
title = "Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment",
abstract = "Objectives: Polymyxins (i.e., polymyxin B and colistin) are used as a last-line therapy to combat multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance in K. pneumoniae is increasingly reported worldwide. This study identified the genetic variations responsible for high-level colistin resistance in MDR K. pneumoniae clinical isolates. Methods: Sixteen MDR K. pneumoniae isolates were obtained from stool samples of 8 patients before and after colistin treatment. Their genomes were sequenced on Illumina MiSeq to determine genetic variations. Results: Fifteen of 16 isolates harboured ISKpn26-like element insertion at nucleotide position 75 of mgrB, abolishing its negative regulation on phoPQ; while colistin-susceptible ATH7 contained intact mgrB and phoQ. Interestingly, each of the 7 mgrB-disrupted, colistin-susceptible isolates contained a nonsynonymous substitution in PhoQ (G39S, L239P, N253T or V446G), potentially impairing its function and intergenically suppressing the effect caused by mgrB inactivation. Additionally, three of the 7 corresponding mgrB-disrupted, colistin-resistant isolates harboured a secondary nonsynonymous substitution in PhoQ (N253P, D438H or T439P). Conclusions: This is the first report of phoQ mutations in mgrB-disrupted, colistin-susceptible K. pneumoniae clinical isolates. We also discovered multiple phoQ mutations in mgrB-disrupted, colistin-resistant strains. Our findings highlight the multifaceted molecular mechanisms of colistin resistance in K. pneumoniae.",
keywords = "Colistin, Genomics, Klebsiella pneumoniae, mgrB, phoQ",
author = "Yan Zhu and Irene Galani and Ilias Karaiskos and Jing Lu and Aye, {Su Mon} and Jiayuan Huang and Yu, {Heidi H.} and Tony Velkov and Helen Giamarellou and Jian Li",
year = "2019",
month = "10",
day = "1",
doi = "10.1016/j.jinf.2019.07.009",
language = "English",
volume = "79",
pages = "312--321",
journal = "Journal of Infection",
issn = "0163-4453",
publisher = "Elsevier",
number = "4",

}

Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment. / Zhu, Yan; Galani, Irene; Karaiskos, Ilias; Lu, Jing; Aye, Su Mon; Huang, Jiayuan; Yu, Heidi H.; Velkov, Tony; Giamarellou, Helen; Li, Jian.

In: Journal of Infection, Vol. 79, No. 4, 01.10.2019, p. 312-321.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment

AU - Zhu, Yan

AU - Galani, Irene

AU - Karaiskos, Ilias

AU - Lu, Jing

AU - Aye, Su Mon

AU - Huang, Jiayuan

AU - Yu, Heidi H.

AU - Velkov, Tony

AU - Giamarellou, Helen

AU - Li, Jian

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Objectives: Polymyxins (i.e., polymyxin B and colistin) are used as a last-line therapy to combat multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance in K. pneumoniae is increasingly reported worldwide. This study identified the genetic variations responsible for high-level colistin resistance in MDR K. pneumoniae clinical isolates. Methods: Sixteen MDR K. pneumoniae isolates were obtained from stool samples of 8 patients before and after colistin treatment. Their genomes were sequenced on Illumina MiSeq to determine genetic variations. Results: Fifteen of 16 isolates harboured ISKpn26-like element insertion at nucleotide position 75 of mgrB, abolishing its negative regulation on phoPQ; while colistin-susceptible ATH7 contained intact mgrB and phoQ. Interestingly, each of the 7 mgrB-disrupted, colistin-susceptible isolates contained a nonsynonymous substitution in PhoQ (G39S, L239P, N253T or V446G), potentially impairing its function and intergenically suppressing the effect caused by mgrB inactivation. Additionally, three of the 7 corresponding mgrB-disrupted, colistin-resistant isolates harboured a secondary nonsynonymous substitution in PhoQ (N253P, D438H or T439P). Conclusions: This is the first report of phoQ mutations in mgrB-disrupted, colistin-susceptible K. pneumoniae clinical isolates. We also discovered multiple phoQ mutations in mgrB-disrupted, colistin-resistant strains. Our findings highlight the multifaceted molecular mechanisms of colistin resistance in K. pneumoniae.

AB - Objectives: Polymyxins (i.e., polymyxin B and colistin) are used as a last-line therapy to combat multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance in K. pneumoniae is increasingly reported worldwide. This study identified the genetic variations responsible for high-level colistin resistance in MDR K. pneumoniae clinical isolates. Methods: Sixteen MDR K. pneumoniae isolates were obtained from stool samples of 8 patients before and after colistin treatment. Their genomes were sequenced on Illumina MiSeq to determine genetic variations. Results: Fifteen of 16 isolates harboured ISKpn26-like element insertion at nucleotide position 75 of mgrB, abolishing its negative regulation on phoPQ; while colistin-susceptible ATH7 contained intact mgrB and phoQ. Interestingly, each of the 7 mgrB-disrupted, colistin-susceptible isolates contained a nonsynonymous substitution in PhoQ (G39S, L239P, N253T or V446G), potentially impairing its function and intergenically suppressing the effect caused by mgrB inactivation. Additionally, three of the 7 corresponding mgrB-disrupted, colistin-resistant isolates harboured a secondary nonsynonymous substitution in PhoQ (N253P, D438H or T439P). Conclusions: This is the first report of phoQ mutations in mgrB-disrupted, colistin-susceptible K. pneumoniae clinical isolates. We also discovered multiple phoQ mutations in mgrB-disrupted, colistin-resistant strains. Our findings highlight the multifaceted molecular mechanisms of colistin resistance in K. pneumoniae.

KW - Colistin

KW - Genomics

KW - Klebsiella pneumoniae

KW - mgrB

KW - phoQ

UR - http://www.scopus.com/inward/record.url?scp=85072355048&partnerID=8YFLogxK

U2 - 10.1016/j.jinf.2019.07.009

DO - 10.1016/j.jinf.2019.07.009

M3 - Article

VL - 79

SP - 312

EP - 321

JO - Journal of Infection

JF - Journal of Infection

SN - 0163-4453

IS - 4

ER -