Multi‐Targeting Carnosic Acid Kills Drug‐Resistant Helicobacter pylori With Narrow‐Spectrum Activity

ABSTRACT Helicobacter pylori ( H. pylori ) is a significant global human pathogen intricately linked to gastritis, peptic ulcers, and gastric cancer. The escalating challenge of antimicrobial resistance and the adverse effects of conventional antibiotics on the gut microbiome necessitate the development of novel, targeted therapeutics. In this study, we demonstrate that carnosic acid (CA), a natural compound derived from traditional Chinese medicine, exhibits potent and specific anti‐ H. pylori activity in vitro, with no detectable resistance observed after prolonged serial passaging. CA also displayed enhanced antibacterial efficacy under physiologically relevant acidic conditions, correlating with its strong inhibition of urease, a key colonization factor for H. pylori . Beyond urease suppression, CA acted through multiple mechanisms, including inhibiting biofilm formation and disrupting mature biofilms, impairing bacterial motility, and compromising cell membrane integrity. In vivo, the combination of CA and omeprazole achieved superior eradication in a mouse model of multidrug‐resistant H. pylori infection compared to standard triple therapy. Furthermore, CA treatment showed negligible toxicity to host tissues and minimal disruption to the diversity and composition of the gut microbiota. These findings position CA as a promising lead compound against drug‐resistant H. pylori , offering a multi‐targeting and microbiota‐friendly strategy to combat this pathogen.