Antibody-Antibiotic Conjugates: Mechanisms, Clinical Progress, and Next-Generation Strategies Against Multidrug-Resistant Bacterial Infections.

The rise of multidrug-resistant (MDR) bacterial pathogens presents a critical challenge to global health, highlighting the need for innovative therapeutic strategies beyond conventional antibiotics. Antibody-antibiotic 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-target 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-mediated bacterial clearance, emphasizing targeted payload release, fragment crystallizable region of the antibody (Fc)-mediated immune engagement, and intracellular delivery. The temporal evolution of AACs is examined, highlighting milestones from early proof-of-concept studies to modern site-specific, humanized constructs and emerging bispecific or dual-payload designs. Furthermore, clinical development is discussed, focusing on pharmacokinetics, pharmacodynamics, safety, efficacy, and regulatory considerations, for example, intracellular infections and biofilm-associated infectious agents. Current challenges, including antigen heterogeneity, immunogenicity, linker-payload optimization, and manufacturing scalability, are critically analyzed, alongside strategies for next-generation AACs. Collectively, AACs represent a transformative platform for precision-targeted antimicrobial therapy, bridging gaps left by conventional antibiotics and offering a promising approach to combating MDR bacterial infections and associated clinical complications.