Antimicrobial resistance: emerging therapeutic alternatives and their translational limitations

Abstract Antimicrobial resistance (AMR) constitutes one of the most pressing threats to global health security and is projected to contribute to up to 10 million deaths annually by 2050, with associated economic losses exceeding US$3.4 trillion in the absence of effective intervention. This critical narrative review synthesizes current evidence on emerging non-antibiotic strategies—including nanoparticles, antimicrobial peptides, bacteriophages, probiotics and postbiotics, CRISPR-Cas systems, immune modulators, plant-derived bioactives, and biomaterial-based platforms—as potential complements or alternatives to conventional antibiotics. Particular attention is given to the mechanisms through which these approaches may overcome or mitigate major resistance determinants, including impaired drug uptake, active efflux, enzymatic inactivation, target-site modification, biofilm-associated tolerance, and horizontal gene transfer. The review further examines the integration of nanomaterials into antimicrobial coatings, hydrogels, implant-associated infection management, tissue-engineering scaffolds, and advanced drug-delivery systems, with emphasis on localized antimicrobial activity, controlled therapeutic release, and the potential to integrate infection control with tissue regeneration. Translational maturity is critically appraised by distinguishing preclinical evidence from interventions that have progressed to human clinical evaluation. Although several bacteriophage, antimicrobial peptide, silver-based, and host-directed therapies have entered clinical development, most emerging strategies remain at the in vitro or preclinical stage and face substantial barriers related to toxicity, pharmacokinetics, delivery, manufacturing scalability, reproducibility, and regulatory complexity. Collectively, current evidence suggests that these approaches are unlikely to constitute universal replacements for conventional antibiotics; rather, their principal value lies in diversifying antimicrobial mechanisms, enabling targeted interventions, and reducing reliance on antibiotics. Realizing their clinical potential will require rigorous validation in well-designed clinical studies, scalable and reproducible manufacturing, and integration within antimicrobial stewardship and One Health frameworks.