Mechanism and Clinical Significance of Metronidazole Resistance in Helicobacter pylori

Wouden, EJ van der; Thijs, J. C.; Kusters, JG; Zwet, AA van; Kleibeuker, JH

doi:10.1080/003655201753265055

Cited by 28 publications

(3 citation statements)

References 18 publications

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“…Metronidazole is a prodrug which is first activated by nitro-reductase (mutated in resistant H. pylori NCTC 11637 strains; Debets-Ossenkopp et al, 1999 ) to produce oxygen radicals toxic to bacteria through DNA damage ( Cederbrant et al, 1992 ; van der Wouden et al, 2001 ). We found that expression of NAD(P)H-dependent oxidoreductase ( rdxA [HP17_RS12480]) was downregulated (log 2 fold-change: −1.51, p = 3.8 × 10 –5 ).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, permutation analyses based on annotation of genes for metronidazole resistance mechanisms and specific metronidazole resistance genes published in the literature showed enrichment for redox (oxygen radical scavenger) and nitro-reductase pathways. Metronidazole is a prodrug which is first activated by nitro-reductase to produce oxygen radicals toxic to bacteria through DNA damage ( van der Wouden et al, 2001 ). Increased nitro-reductase activity in theory leads to reduced metronidazole resistance.…”

Section: Discussionmentioning

confidence: 99%

“…In addition we also found Sod expression to be downregulated with elevated temperature. Sod contributes to metronidazole resistance through mitigating oxygen radical related damage and increased Sod levels have been associated with development of metronidazole resistance ( Wassmann and Bruchhaus, 2000 ; van der Wouden et al, 2001 ). Interestingly, we observed an increased expression of a negative transcription regulator of Sod , Fur , which may also contribute to decreased Sod expression.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Temperature on Metronidazole Resistance in Helicobacter pylori

et al. 2021

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Efficacy of Helicobacter pylori (H. pylori) eradication therapy has declined due to rapid rises in antibiotic resistance. We investigated how increased temperature affected H. pylori (NCTC 11637) growth and its sensitivity to metronidazole in vitro. We performed transcriptomic profiling using RNA-sequencing to identify differentially expressed genes (DEGs) associated with increased temperature. Transcriptional pathways involved in temperature-driven metronidazole resistance changes were analyzed through bioinformatic and literature curation approaches. We showed that H. pylori growth was inhibited at 41°C and inhibition was more apparent with prolonged incubation. Resistance to metronidazole was also reduced—minimum inhibitory concentration for metronidazole decreased from > 256 μg/ml at 37°C to 8 μg/ml at 41°C after culturing for 3 days. RNA-sequencing results, which were highly concordant within treatment conditions, revealed more than one third of genes (583/1,552) to be differentially expressed at increased temperatures with similar proportions up and down-regulated. Quantitative real-time PCR validation for 8 out of 10 DEGs tested gave consistent direction in gene expression changes. We found enrichment for redox and oxygen radical pathways, highlighting a mechanistic pathway driving temperature-related metronidazole resistance. Independent literature review of published genes associated with metronidazole resistance revealed 46 gene candidates, 21 of which showed differential expression and 7 out of 9 DEGs associated with “redox” resistance pathways. Sanger sequencing did not detect any changes in genetic sequences for known resistance genes rdxA, frxA nor fdxB. Our findings suggest that temperature increase can inhibit the growth and reduce H. pylori resistance to metronidazole. Redox pathways are possible potential drivers in metronidazole resistance change induced by temperature. Our study provides insight into potential novel approaches in treating antibiotic resistant H. pylori.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effect of Temperature on Metronidazole Resistance in Helicobacter pylori

et al. 2021

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Mechanisms of Resistance to Antibacterial Agents

Bradford,

Castanheira

2023

ClinMicroNow

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Bacterial pathogens have developed resistance to antibacterial agents via multiple routes. The emergence of antimicrobial resistance phenotypes is directly linked to the use of any given anti microbial agent. Resistance to aminoglycosides occurs by several different mechanisms that can coexist in the same bacterial cell. β‐Lactam antibiotics act by inhibiting penicillin‐binding proteins, which are transpeptidases and transglycosylases that synthesize the peptidogly can that composes the bacterial cell wall. The main bacterial resistance mechanism against fluoroquinolonesis is the alteration of their target in the deoxyribonucleic acid synthesis process. Tetracyclines are bacteriostatic antibiotics that inhibit bacterial growth by binding to the ribosome, thereby preventing protein synthesis. Nitrofurantoin is a synthetic antibacterial agent that is only used in the treatment of urinary tract infections. Rifampin is particularly active against Gram‐positive bacteria and mycobacteria. Daptomycin is a cyclic lipopeptide antibiotic with activity exclusively against Gram‐positive bacteria.

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Biochemical mechanisms of resistance to antimicrobial drugs

Biochemistry and Molecular Biology of Antimicrobial Drug Action

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Mechanism and Clinical Significance of Metronidazole Resistance in Helicobacter pylori

Cited by 28 publications

References 18 publications

Effect of Temperature on Metronidazole Resistance in Helicobacter pylori

Effect of Temperature on Metronidazole Resistance in Helicobacter pylori

Mechanisms of Resistance to Antibacterial Agents

Biochemical mechanisms of resistance to antimicrobial drugs

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