Beyond Antibiotics: Bacteriophage Therapy, Antimicrobial Peptides, and CRISPR-Based Strategies Against Resistant Bacteria

Abstract

Antimicrobial resistance (AMR) is among the leading threats to global health. Bacterial AMR was associated with an estimated 4.71 million deaths in 2021, and forecasts suggest the toll will rise substantially by 2050. At the same time, the pipeline of new antibiotic classes remains thin, and most recent approvals are modifications of existing scaffolds. This review summarizes the principal mechanisms by which bacteria resist antibiotics and then examines three non-conventional approaches that have moved from concept toward clinical translation: bacteriophage therapy (including phage-derived endolysins), antimicrobial peptides (AMPs), and CRISPR-Cas-based antimicrobials. For each approach we discuss mode of action, the strongest available clinical or preclinical evidence, and the main barriers, including bacterial counter-resistance, delivery, stability, safety, and regulation. We also briefly consider artificial intelligence-guided discovery as a complementary route. We conclude that these strategies are unlikely to replace antibiotics outright, but may serve as adjuncts or salvage options for infections with few remaining treatment choices, provided that standardized trials, manufacturing pathways, and stewardship frameworks mature in parallel.