High salt condition alters LPS synthesis and induces the emergence of drug resistance mutations in <i>Helicobacter pylori</i>

The burgeoning emergence of drug-resistant <i>Helicobacter pylori</i> strains poses a significant challenge to the clinical success of eradication therapies and is primarily attributed to mutations within drug-targeting genes that lead to antibiotic resistance. This study investigated the effect of high salt conditions on the occurrence of drug-resistance mutations in <i>H. pylori</i>. We found that high salt condition significantly amplifies the frequency of drug resistance mutations in <i>H. pylori</i>. This can be chiefly attributed to our discovery indicating that high salt concentration results in elevated reactive oxygen species (ROS) levels, initiating DNA damage within <i>H. pylori</i>. Mechanistically, high salt condition suppresses lipopolysaccharide (LPS) synthesis gene expression, inducing alterations in the LPS structure and escalating outer membrane permeability. This disruption of LPS synthesis attenuates the expression and activity of SodB, facilitates increased ROS levels, and consequently increases the drug resistance mutation frequency. Impairing LPS synthesis engenders a reduction in intracellular iron levels, leading to diminished holo-Fur activity and increased apo-Fur activity, which represses the expression of SodB directly. Our findings suggest a correlation between high salt intake and the emergence of drug resistance in the human pathogen <i>H. pylori</i>, implying that dietary choices affect the risk of emergence of antimicrobial resistance.IMPORTANCEDrug resistance mutations mainly contribute to the emergence of clinical antibiotic-resistant <i>Helicobacter pylori,</i> a bacterium linked to stomach ulcers and cancer. In this study, we explored how elevated salt conditions influence the emergence of drug resistance in <i>H. pylori</i>. We demonstrate that <i>H. pylori</i> exhibits an increased antibiotic resistance mutation frequency when exposed to a high salt environment. We observed an increase in reactive oxygen species (ROS) under high salt conditions, which can cause DNA damage and potentially lead to mutations. Moreover, our results showed that high salt condition alters the bacterium's lipopolysaccharide (LPS) synthesis, leading to a reduced expression of SodB in a Fur-dependent manner. This reduction, in turn, elevates ROS levels, culminating in a higher frequency of drug-resistance mutations. Our research underscores the critical need to consider environmental influences, such as diet and lifestyle, in managing bacterial infections and combating the growing challenge of antibiotic resistance.