Innovative perspectives on the discovery of small molecule antibiotics

Antibiotics are crucial for modern medicine, but multidrug-resistant (MDR) infections pose a threat to their effectiveness. Resistance evolution shortens antibiotic lifespans, limiting investment returns and slowing new approvals. The World Health Organization (WHO) has set four innovation criteria for the development of new antibiotics: novelty regarding chemical class, molecular target, mode of action (MoA), and lack of cross-resistance with current antibiotics. This review explores innovative discovery approaches, including AI-driven screening, metagenomics, and target-based strategies, to develop novel antibiotics that meet these criteria and combat MDR infections. The top three bacteria prioritized as critically in need of new antibiotic therapies belong to the Gram-negative group. To fulfill the WHO criteria, cutting-edge alternatives to classic antibiotics, such as biologics, could be considered. However, innovation applied to small-molecule antibiotics, chemically defined active compounds of natural or synthetic origin, can benefit from accumulated knowledge and lessons learned from previously exploited approaches.