Emad M. Abdallah, Abdulrahman Mohammed Alhudhaibi, Mahmoud M. Dahab, Abdullah Al Noman, Pranav Sharma, Tarek H. Taha, Muhammad Nawaz
Antimicrobial resistance (AMR) remains one of the most serious global threats to public health, driven by the rapid emergence and dissemination of multidrug-resistant bacterial pathogens that compromise existing antibiotic therapies. In response, the World Health Organization (WHO) has defined priority lists of antibiotic-resistant bacteria to guide research, innovation, and drug development efforts. This narrative review synthesizes current knowledge on the molecular mechanisms underlying resistance in WHO-priority pathogens, including reduced membrane permeability, efflux pump overexpression, enzymatic drug inactivation, target modification, biofilm formation, and horizontal gene transfer. Beyond mechanistic insights, we critically evaluate the therapeutic limitations of conventional antibiotics, the failure of traditional discovery pipelines, and the growing clinical and economic burden of resistant infections. Emerging strategies, including artificial intelligence-assisted drug discovery, phage therapy, antimicrobial peptides, CRISPR-based systems, resistance-modifying combinations, and natural product-derived compounds and plant compounds, are assessed with emphasis on pharmacological feasibility, translational challenges, and clinical relevance. Particular attention is given to issues of delivery, toxicity, dosing optimization, resistance emergence, regulatory barriers, and real-world implementation. Finally, we highlight the central role of antimicrobial stewardship, surveillance, and a One Health framework integrating human, animal, and environmental sectors in mitigating resistance and sustaining therapeutic effectiveness. Collectively, this review underscores that addressing WHO-priority pathogens will require integrated, multidisciplinary strategies that bridge molecular biology, pharmacology, clinical translation, and public health.