Antibacterial Immunotherapy: Mechanistic Insights, Emerging Therapeutic Strategies, and Clinical Translation

Antimicrobial resistance (AMR) continues to compromise the effectiveness of conventional antibacterial therapy, driving the development of therapeutic strategies that extend beyond direct antibiotic-mediated bacterial killing. Multidrug-resistant (MDR) pathogens evade treatment through diverse mechanisms, including enzymatic drug inactivation, target modification, efflux pump overexpression, biofilm formation, and persisters development. AMR results in chronic and recurrent infections, prolonged hospitalization, increased healthcare costs, and elevated morbidity and mortality, underscoring the need for innovative therapeutic approaches that target both the pathogen and the host. To bridge the dynamic interplay between bacterial pathogens and the host immune system with emerging therapeutic innovations, this narrative review first examines the biological mechanisms underlying bacterial resistance. It then explores therapeutic strategies beyond conventional antibiotics, providing an overview of current approaches and their limitations, including drug repurposing, bacteriophage therapy, and CRISPR-Cas technology. The review subsequently focuses on antibacterial immunotherapy, discussing a broad range of emerging approaches, including probiotics, monoclonal antibodies, cell-based therapies, host-directed therapies, aptamers, nanotechnology-based platforms, cytokine-based therapies, and antimicrobial peptides. An integrated overview of preclinical evidence, clinical studies, and FDA-approved therapies is presented to assess the translational potential of immunotherapy strategies in combating AMR. Scientific, regulatory, manufacturing, and implementation challenges that influence their successful translation into clinical practice are discussed throughout. By integrating the biological basis of host-pathogen interactions with emerging antibacterial therapeutics and their translational development, this review provides a comprehensive framework for evaluating innovative strategies against antimicrobial resistance. In contrast to modality-focused reviews, it offers a unified perspective that highlights the complementary roles of pathogen-targeted and host-directed interventions and identifies future opportunities to improve the prevention and management of multidrug-resistant bacterial infections.