Combating Antimicrobial Resistance: Emerging Non-Traditional Therapeutics, Clinical Translation Challenges, and...

Antimicrobial resistance (AMR) has emerged as one of the most severe global health threats. The rapid expansion of multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens compromises the effectiveness of conventional antibiotics. Globally, ESKAPE organisms (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) have led to therapeutic failure, prolonged hospitalization, and increased mortality rates. This review identifies the molecular mechanisms, including enzymatic antibiotic inactivation, efflux pump overexpression, biofilm formation, and horizontal gene transfer, that underline the resistance of disseminated pathogens to antibiotics in clinical, agricultural, and environmental settings. Antibiotic overuse and pharmaceutical and agricultural discharges create persistent reservoirs for the dissemination of AMR genes. Furthermore, we evaluated the non-traditional antibacterial efficacy of antimicrobial peptides, bacteriophage therapy, monoclonal antibodies, probiotics, fecal microbiota transplantation, anti-virulence agents, CRISPR-Cas precision antimicrobials, and nanotechnology-based drug delivery platforms. Current preclinical and clinical evidence indicates the eradication of resistant pathogens, disruption of biofilms, and preservation of host microbiota, thereby reducing the selective pressure associated with broad-spectrum antibiotics. Despite these advances, major translational barriers, such as pharmacokinetic instability, manufacturing limitations, and insufficient clinical validation, restrict the implementation of the framework. In the future, the AMR management framework will require precision medicine, artificial intelligence, and One Health-based integration via multidisciplinary collaboration.