Microbiome mining, AI, and experimental strategies accelerate novel antimicrobial discovery.

The escalating threat of antimicrobial resistance (AMR) to bacterial and fungal pathogens severely compromises public health, with the rate of new antimicrobial development lagging far behind resistance emergence. Current therapeutic options are limited by microbial dysbiosis, systemic toxicity, and poor efficacy against persistent infections. This critical gap necessitates the exploration of novel sources and advanced discovery methodologies to identify new antimicrobial peptides (AMPs) and small molecules with distinct mechanisms of action.

This review synthesized current strategies for discovering novel antimicrobials by mining diverse human and environmental microbiomes. It focused on methods used to extract biosynthetic gene clusters (BGCs) and antimicrobial peptides and proteins. The authors examined both classical approaches and modern techniques, including artificial intelligence (AI)-enabled computational methods and innovative experimental strategies, to prioritize candidates and identify active compounds against priority pathogens. The scope included highlighting the urgent need for expanded antifungal discovery efforts.

The review highlighted how the genomics big data revolution has significantly advanced antimicrobial discovery, particularly in identifying novel antimicrobial peptides and proteins from microbiomes. It detailed how advanced computational methods, often augmented by AI, are increasingly effective in predicting and prioritizing promising candidates from complex genomic data. These approaches have successfully revealed new small molecules and proteins active against critical pathogens, often uncovering novel modes of action. A key finding emphasized the severe deficit in antifungal discovery, noting the limited number of therapeutic classes available and the slow pace of pipeline replenishment. This underscores a critical, unmet medical need. The authors noted that these integrated strategies are crucial for overcoming the stagnation in antimicrobial development.

The integration of genomics, AI, and innovative experimental strategies is proving essential for identifying novel antimicrobial peptides and proteins from diverse microbiomes, addressing the critical gap in drug discovery.