Analysis of core protein clusters identifies candidate variable sites conferring metronidazole resistance in Helicobacter pylori

Research output: Contribution to journalArticle

Abstract

Background
Metronidazole is one of the first-line drugs of choice in the standard triple therapy used to eradicate Helicobacter pylori infection. Hence, the global emergence of metronidazole resistance in Hp poses a major challenge to health professionals. Inactivation of RdxA is known to be a major mechanism of conferring metronidazole resistance in H. pylori. However, metronidazole resistance can also arise in H. pylori strains expressing functional RdxA protein, suggesting that there are other mechanisms that may confer resistance to this drug.

Methods
We performed whole-genome sequencing on 121 H. pylori clinical strains, among which 73 were metronidazole-resistant. Sequence-alignment analysis of core protein clusters derived from clinical strains containing full-length RdxA was performed. Variable sites in each alignment were statistically compared between the resistant and susceptible groups to determine candidate genes along with their respective amino-acid changes that may account for the development of metronidazole resistance in H. pylori.

Results
Resistance due to RdxA truncation was identified in 34% of metronidazole-resistant strains. Analysis of core protein clusters derived from the remaining 48 metronidazole-resistant strains and 48 metronidazole-susceptible identified four variable sites significantly associated with metronidazole resistance. These sites included R16H/C in RdxA, D85N in the inner-membrane protein RclC (HP0565), V265I in a biotin carboxylase protein (HP0370) and A51V/T in a putative threonylcarbamoyl–AMP synthase (HP0918).

Conclusions
Our approach identified new potential mechanisms for metronidazole resistance in H. pylori that merit further investigation.
Original languageEnglish
Article numbergoy048
Pages (from-to)1-8
Number of pages8
JournalGastroenterology Report
DOIs
Publication statusPublished - 2 Jan 2019

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Metronidazole
Helicobacter pylori
Proteins
biotin carboxylase
Sequence Alignment
Helicobacter Infections
Drug Resistance
Sequence Analysis
Membrane Proteins
Genome
Amino Acids

Cite this

@article{e57f78efd35e4170b2213405f9159ab6,
title = "Analysis of core protein clusters identifies candidate variable sites conferring metronidazole resistance in Helicobacter pylori",
abstract = "BackgroundMetronidazole is one of the first-line drugs of choice in the standard triple therapy used to eradicate Helicobacter pylori infection. Hence, the global emergence of metronidazole resistance in Hp poses a major challenge to health professionals. Inactivation of RdxA is known to be a major mechanism of conferring metronidazole resistance in H. pylori. However, metronidazole resistance can also arise in H. pylori strains expressing functional RdxA protein, suggesting that there are other mechanisms that may confer resistance to this drug.MethodsWe performed whole-genome sequencing on 121 H. pylori clinical strains, among which 73 were metronidazole-resistant. Sequence-alignment analysis of core protein clusters derived from clinical strains containing full-length RdxA was performed. Variable sites in each alignment were statistically compared between the resistant and susceptible groups to determine candidate genes along with their respective amino-acid changes that may account for the development of metronidazole resistance in H. pylori.ResultsResistance due to RdxA truncation was identified in 34{\%} of metronidazole-resistant strains. Analysis of core protein clusters derived from the remaining 48 metronidazole-resistant strains and 48 metronidazole-susceptible identified four variable sites significantly associated with metronidazole resistance. These sites included R16H/C in RdxA, D85N in the inner-membrane protein RclC (HP0565), V265I in a biotin carboxylase protein (HP0370) and A51V/T in a putative threonylcarbamoyl–AMP synthase (HP0918).ConclusionsOur approach identified new potential mechanisms for metronidazole resistance in H. pylori that merit further investigation.",
author = "Chua, {Eng Guan} and Aleksandra Debowski and Katherine Webberley and Fanny Peters and Binit Lamichhane and Loke, {Mun Fai} and Jamuna Vadivelu and Tay, {Chin Yen} and Barry Marshall and Wise, {Michael J.}",
year = "2019",
month = "1",
day = "2",
doi = "10.1093/gastro/goy048",
language = "English",
pages = "1--8",
journal = "Gastroenterology Report",
issn = "2052-0034",
publisher = "Oxford Journals",

}

TY - JOUR

T1 - Analysis of core protein clusters identifies candidate variable sites conferring metronidazole resistance in Helicobacter pylori

AU - Chua, Eng Guan

AU - Debowski, Aleksandra

AU - Webberley, Katherine

AU - Peters, Fanny

AU - Lamichhane, Binit

AU - Loke, Mun Fai

AU - Vadivelu, Jamuna

AU - Tay, Chin Yen

AU - Marshall, Barry

AU - Wise, Michael J.

PY - 2019/1/2

Y1 - 2019/1/2

N2 - BackgroundMetronidazole is one of the first-line drugs of choice in the standard triple therapy used to eradicate Helicobacter pylori infection. Hence, the global emergence of metronidazole resistance in Hp poses a major challenge to health professionals. Inactivation of RdxA is known to be a major mechanism of conferring metronidazole resistance in H. pylori. However, metronidazole resistance can also arise in H. pylori strains expressing functional RdxA protein, suggesting that there are other mechanisms that may confer resistance to this drug.MethodsWe performed whole-genome sequencing on 121 H. pylori clinical strains, among which 73 were metronidazole-resistant. Sequence-alignment analysis of core protein clusters derived from clinical strains containing full-length RdxA was performed. Variable sites in each alignment were statistically compared between the resistant and susceptible groups to determine candidate genes along with their respective amino-acid changes that may account for the development of metronidazole resistance in H. pylori.ResultsResistance due to RdxA truncation was identified in 34% of metronidazole-resistant strains. Analysis of core protein clusters derived from the remaining 48 metronidazole-resistant strains and 48 metronidazole-susceptible identified four variable sites significantly associated with metronidazole resistance. These sites included R16H/C in RdxA, D85N in the inner-membrane protein RclC (HP0565), V265I in a biotin carboxylase protein (HP0370) and A51V/T in a putative threonylcarbamoyl–AMP synthase (HP0918).ConclusionsOur approach identified new potential mechanisms for metronidazole resistance in H. pylori that merit further investigation.

AB - BackgroundMetronidazole is one of the first-line drugs of choice in the standard triple therapy used to eradicate Helicobacter pylori infection. Hence, the global emergence of metronidazole resistance in Hp poses a major challenge to health professionals. Inactivation of RdxA is known to be a major mechanism of conferring metronidazole resistance in H. pylori. However, metronidazole resistance can also arise in H. pylori strains expressing functional RdxA protein, suggesting that there are other mechanisms that may confer resistance to this drug.MethodsWe performed whole-genome sequencing on 121 H. pylori clinical strains, among which 73 were metronidazole-resistant. Sequence-alignment analysis of core protein clusters derived from clinical strains containing full-length RdxA was performed. Variable sites in each alignment were statistically compared between the resistant and susceptible groups to determine candidate genes along with their respective amino-acid changes that may account for the development of metronidazole resistance in H. pylori.ResultsResistance due to RdxA truncation was identified in 34% of metronidazole-resistant strains. Analysis of core protein clusters derived from the remaining 48 metronidazole-resistant strains and 48 metronidazole-susceptible identified four variable sites significantly associated with metronidazole resistance. These sites included R16H/C in RdxA, D85N in the inner-membrane protein RclC (HP0565), V265I in a biotin carboxylase protein (HP0370) and A51V/T in a putative threonylcarbamoyl–AMP synthase (HP0918).ConclusionsOur approach identified new potential mechanisms for metronidazole resistance in H. pylori that merit further investigation.

U2 - 10.1093/gastro/goy048

DO - 10.1093/gastro/goy048

M3 - Article

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EP - 8

JO - Gastroenterology Report

JF - Gastroenterology Report

SN - 2052-0034

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