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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\n                    <jats:italic>yqgB<\/jats:italic>\n                    gene as a crucial target for restoring colistin susceptibility in\n                    <jats:italic>mcr<\/jats:italic>\n                    \u2010positive bacteria, particularly under acidic conditions.\n                    <jats:italic>yqgB<\/jats:italic>\n                    deficiency drastically enhances colistin's bactericidal effect, which is attributed to the alteration of phospholipid composition and reduction in lipopolysaccharide modification. Using deep learning\u2010based screening, we find that H\n                    <jats:sub>2<\/jats:sub>\n                    receptor antagonists (ebrotidine, ranitidine and famotidine) can act as dual inhibitors of MCR and YqgB proteins, thus exhibiting excellent synergistic activity with colistin against\n                    <jats:italic>mcr<\/jats:italic>\n                    \u2010positive 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\n                    <jats:italic>mcr<\/jats:italic>\n                    \u2010positive pathogens, the co\u2010administration 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\n                    <jats:italic>mcr<\/jats:italic>\n                    \u2010mediated colistin resistance and offer a promising therapeutic strategy for the treatment of MDR bacterial infections.\n                  <\/jats:p>","DOI":"10.1002\/advs.202514165","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:01:53Z","timestamp":1773014513000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of H\n                    <sub>2<\/sub>\n                    Receptor Antagonists as Colistin Enhancers by Targeting Acid Stress Response"],"prefix":"10.1002","volume":"13","author":[{"given":"Jinju","family":"Cai","sequence":"first","affiliation":[{"name":"Jiangsu Co\u2010innovation Center For Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengping","family":"He","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center For Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianya","family":"Luo","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center For Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center For Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center For Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianing","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center For Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center For Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou China"},{"name":"Joint International Research Laboratory of Agriculture and Agri\u2010Product Safety the Ministry of Education of China Yangzhou University  Yangzhou China"},{"name":"Institute of Comparative Medicine Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9622-6471","authenticated-orcid":false,"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Co\u2010innovation Center For Prevention and Control of Important Animal Infectious Diseases and Zoonoses College of Veterinary Medicine Yangzhou University  Yangzhou China"},{"name":"Joint International Research Laboratory of Agriculture and Agri\u2010Product Safety the Ministry of Education of China Yangzhou University  Yangzhou China"},{"name":"Institute of Comparative Medicine Yangzhou University  Yangzhou 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