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Gastric Mucosa Quantitative Polymerase Chain Reaction Analysis for Detecting Helicobacter pylori and Antibiotic Resistance

Gastric Mucosa Quantitative Polymerase Chain Reaction Analysis for Detecting Helicobacter pylori and Antibiotic Resistance

Published on: March 7, 2025

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

Eng-Guan Chua¹, Aleksandra W Debowski^1,2, K Mary Webberley¹

¹The Marshall Centre for Infectious Diseases Research and Training, University of Western Australia, Perth, Western Australia, Australia.

Gastroenterology Report

|February 23, 2019

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.

Insights

New mechanisms of metronidazole resistance in Helicobacter pylori were identified beyond RdxA inactivation. Whole-genome sequencing revealed specific genetic variations linked to drug resistance, offering new targets for treatment strategies.

Area of Science:

Microbiology
Genomics
Drug Resistance

Background:

Metronidazole is a key drug for eradicating Helicobacter pylori (H. pylori) infections.
Emerging metronidazole resistance in H. pylori presents a significant clinical challenge.
While RdxA inactivation is a known resistance mechanism, other pathways exist.

Purpose of the Study:

To investigate novel mechanisms contributing to metronidazole resistance in H. pylori.
To identify genetic variations associated with metronidazole resistance beyond RdxA mutations.

Main Methods:

Whole-genome sequencing of 121 H. pylori clinical strains (73 resistant, 48 susceptible).
Sequence alignment analysis of core protein clusters.
Statistical comparison of variable sites between resistant and susceptible strains.

Main Results:

RdxA truncation accounted for 34% of metronidazole resistance.
Four novel variable sites significantly associated with resistance were identified: R16H/C in RdxA, D85N in RclC (HP0565), V265I in HP0370, and A51V/T in HP0918.
These sites involve proteins including an inner-membrane protein and a biotin carboxylase protein.

Conclusions:

Identified novel genetic variations potentially conferring metronidazole resistance in H. pylori.
These findings suggest new mechanisms of resistance that require further investigation.
Potential for new therapeutic targets to overcome metronidazole resistance.

Read full analysis

Keywords:

Helicobacter pylori antibiotic resistance core protein clusters metronidazole sequence alignment whole-genome sequencing

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