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Trends in Helicobacter pylori resistance to clarithromycin: from phenotypic to genomic approaches
Andreia T Marques1, Jorge M B Vítor1,2, Andrea Santos3
1Host-Pathogen Interactions Unit, Research Institute for Medicines (iMed-ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
Abstract:
For a long time Helicobacter pylori infections have been treated using the macrolide antibiotic, clarithromycin. Clarithromycin resistance is increasing worldwide and is the most common cause of H. pylori treatment failure. Here we review the mechanisms of antibiotic resistance to clarithromycin, detailing the individual and combinations of point mutations found in the 23S rRNA gene associated with resistance. Additionally, we consider the methods used to detect clarithromycin resistance, emphasizing the use of high-throughput next-generation sequencing methods, which were applied to 17 newly sequenced pairs of H. pylori strains isolated from the antrum and corpus of a recent colonized paediatric population. This set of isolates was composed of six pairs of resistant strains whose phenotype was associated with two point mutations found in the 23S rRNA gene: A2142C and A2143G. Other point mutations were found simultaneously in the same gene, but, according to our results, it is unlikely that they contribute to resistance. Further, among susceptible isolates, genomic variations compatible with mutations previously associated with clarithromycin resistance were detected. Exposure to clarithromycin may select low-frequency variants, resulting in a progressive increase in the resistance rate due to selection pressure.
Insights
Clarithromycin resistance in Helicobacter pylori is rising, often due to specific 23S rRNA gene mutations. New sequencing methods help detect this resistance, crucial for effective H. pylori treatment.
Area of Science:
- Microbiology
- Genetics
- Pharmacology
Background:
- Clarithromycin is a key antibiotic for treating *Helicobacter pylori* infections.
- Increasing clarithromycin resistance is a major cause of treatment failure worldwide.
- Understanding resistance mechanisms is vital for developing effective therapeutic strategies.
Purpose of the Study:
- To review mechanisms of clarithromycin resistance in *H. pylori*.
- To detail point mutations in the 23S rRNA gene associated with resistance.
- To evaluate methods for detecting clarithromycin resistance, including next-generation sequencing.
Main Methods:
- Review of existing literature on clarithromycin resistance mechanisms.
- Analysis of point mutations in the 23S rRNA gene.
- Application of high-throughput next-generation sequencing to newly sequenced *H. pylori* isolates.
Main Results:
- Specific point mutations (A2142C and A2143G) in the 23S rRNA gene are strongly associated with clarithromycin resistance.
- Other detected mutations in the same gene are unlikely to contribute significantly to resistance.
- Genomic variations suggesting pre-existing resistance mutations were found in susceptible isolates, indicating potential for rapid selection.
Conclusions:
- Clarithromycin resistance in *H. pylori* is primarily driven by specific mutations in the 23S rRNA gene.
- Next-generation sequencing offers a powerful tool for detecting clarithromycin resistance.
- Clarithromycin exposure can select for low-frequency resistance variants, leading to increased resistance rates over time.
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