Prevalence and Molecular Mechanisms of Amoxicillin Resistance Among Clinical <i>Helicobacter pylori</i> Isolates in Southwest China

Helicobacter pylori remains a major gastric pathogen associated with chronic gastritis, peptic ulcer disease, and gastric carcinoma worldwide. Although amoxicillin is a cornerstone of H. pylori eradication regimens, rising resistance rates are undermining treatment efficacy. The molecular mechanisms underlying amoxicillin resistance in Southwest China remain incompletely characterized. In this study, we analyzed 1153 H. pylori isolates obtained from 2181 patients, randomly selecting 23 amoxicillin-resistant and 38 susceptible strains for whole-genome sequencing. Antimicrobial susceptibility testing revealed an overall resistance prevalence of 8.3% (minimum inhibitory concentration range: 0.016-32 µg/mL). Notably, amino acid substitutions in the pbp1a gene, specifically N562Y/H and S414R/N, along with novel variants E406K and G597S/A, were significantly enriched in amoxicillin-resistant strains. Furthermore, the number of mutations was positively correlated with the minimum inhibitory concentration. Proteomic analysis following amoxicillin exposure revealed 39 differentially expressed proteins, including those involved in peptidoglycan repair, nickel uptake, and central metabolism. This comprehensive genomic and proteomic study elucidates the mutational spectrum and adaptive protein responses that drive amoxicillin resistance in H. pylori in Southwestern China. These findings provide potential biomarkers for resistance surveillance and offer insights into targeted therapeutic strategies.