Non-antibiotic therapeutic approaches for antimicrobial resistance: current evidence and future directions

Antimicrobial resistance (AMR) is a global health challenge that reduces the effectiveness of existing antibiotics, leading to increased morbidity, mortality and healthcare costs worldwide. The lack of the development of novel classes of antibiotics has led to an increased interest in non-antibiotic therapeutic approaches that focus on bacterial virulence, host-pathogen interactions, microbial ecology, and resistance mechanisms.

This review summarizes the current evidence on non-antibiotic therapeutics including bacteriophages, antimicrobial peptides, anti-virulence agents, monoclonal antibodies, microbiome-based therapies, CRISPR-Cas systems, nanoparticles, photodynamic therapy, repurposed non-antibiotic drugs and combination strategies. We performed a literature search on PubMed, Embase, Scopus, Web of Science, and Google Scholar until May 2026. Though several approaches have demonstrated promising biological activity and favorable safety profiles, clinical evidence remains limited and heterogeneous.

Non-antibiotic therapeutics are vital adjunctive, salvage and precision approaches to the challenge of AMR. However, most strategies are still at an early translational stage with a paucity of high-quality randomized clinical evidence. Barriers include delivery, manufacturing complexity, regulatory uncertainty, cost, and lack of long-term safety data. Further progress will depend on standardization of production, better delivery platforms, well-designed multicentric clinical trials, and incorporation into antimicrobial stewardship and precision medicine frameworks.