Discovery of H ₂ Receptor Antagonists as Colistin Enhancers by Targeting Acid Stress Response

ABSTRACT Plasmid‐mediated colistin resistance gene mcr has markedly diminished the effectiveness of colistin in managing multidrug‐resistant (MDR) Gram‐negative bacterial infections. Employing antibiotic adjuvants to revive colistin susceptibility offers a valuable solution to address this issue. Intestinal pathogens have evolved sophisticated acid resistance systems to withstand the acidic environment, a key adaptation that facilitates subsequent infection. Utilizing transposon sequencing, here we identify yqgB gene as a crucial target for restoring colistin susceptibility in mcr ‐positive bacteria, particularly under acidic conditions. yqgB deficiency drastically enhances colistin's bactericidal effect, which is attributed to the alteration of phospholipid composition and reduction in lipopolysaccharide modification. Using deep learning‐based screening, we find that H ₂ receptor antagonists (ebrotidine, ranitidine and famotidine) can act as dual inhibitors of MCR and YqgB proteins, thus exhibiting excellent synergistic activity with colistin against mcr ‐positive bacteria under both neutral and acidic conditions. This combination not only bolsters colistin's efficacy but also impedes the evolution and spread of colistin resistance. In animal models infected with mcr ‐positive pathogens, the co‐administration of ranitidine and colistin demonstrates superior therapeutic outcomes against both systemic and intestinal infections. Our findings highlight the potential of targeting the bacterial acid stress response system to counteract mcr ‐mediated colistin resistance and offer a promising therapeutic strategy for the treatment of MDR bacterial infections.