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Antibody\u2013antibiotic conjugates (AACs) combine the high specificity of monoclonal antibodies with the potent bactericidal activity of antibiotics, offering targeted delivery to extracellular and intracellular bacteria while minimizing off\u2010target toxicity. The present review provides a comprehensive analysis of AAC development, including key components, such as antigen selection, antibody engineering, linker chemistry, antibiotic payload optimization, and bioconjugation strategies. We summarize the mechanistic principles underlying AAC\u2010mediated bacterial clearance, emphasizing targeted payload release, fragment crystallizable region of the antibody (Fc)\u2010mediated immune engagement, and intracellular delivery. The temporal evolution of AACs is examined, highlighting milestones from early proof\u2010of\u2010concept studies to modern site\u2010specific, humanized constructs and emerging bispecific or dual\u2010payload designs. Furthermore, clinical development is discussed, focusing on pharmacokinetics, pharmacodynamics, safety, efficacy, and regulatory considerations, for example, intracellular infections and biofilm\u2010associated infectious agents. Current challenges, including antigen heterogeneity, immunogenicity, linker\u2010payload optimization, and manufacturing scalability, are critically analyzed, alongside strategies for next\u2010generation AACs. Collectively, AACs represent a transformative platform for precision\u2010targeted antimicrobial therapy, bridging gaps left by conventional antibiotics and offering a promising approach to combating MDR bacterial infections and associated clinical complications.<\/jats:p>","DOI":"10.1002\/mbo3.70234","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T05:20:12Z","timestamp":1771478412000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antibody\u2013Antibiotic Conjugates: Mechanisms, Clinical Progress, and Next\u2010Generation Strategies Against Multidrug\u2010Resistant Bacterial Infections"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7699-7765","authenticated-orcid":false,"given":"Parvin","family":"Askari","sequence":"first","affiliation":[{"name":"Infectious Diseases Research Center Birjand University of Medical Sciences Birjand 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