# Antibody–Antibiotic Conjugates: Mechanisms, Clinical Progress, and Next‐Generation Strategies Against Multidrug‐Resistant Bacterial Infections

## TL;DR

Antibody-antibiotic conjugates combine antibodies and antibiotics to target drug-resistant bacteria more effectively, reducing side effects and improving treatment outcomes.

## Contribution

This paper reviews the development and clinical progress of antibody-antibiotic conjugates as a novel strategy for combating multidrug-resistant bacterial infections.

## Key findings

- Antibody-antibiotic conjugates enable targeted antibiotic delivery to multidrug-resistant bacteria.
- AACs show improved efficacy against intracellular and biofilm-associated infections.
- AACs reduce systemic toxicity compared to conventional antibiotics.

## Abstract

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.

Antibody–antibiotic conjugates enable targeted delivery of antibiotics to multidrug‐resistant bacteria by combining monoclonal antibody specificity with controlled intracellular drug release. This strategy improves efficacy against intracellular and biofilm‐associated infections while reducing systemic toxicity.