Mining the code of life for new antibiotics

Antimicrobial resistance (AMR) is outpacing antibiotic development, creating an urgent need for discovery strategies that are faster, broader, and more systematic. Here, we review the transition from classical "dirt mining" and phenotypic screening toward digital discovery approaches that treat chemical structures and biological sequences as searchable, engineerable substrates for antibiotic innovation. Modern extensions of conventional screening, including in situ cultivation, co-culture, and microfluidics, have broadened access to previously uncultured microbes. Computer-aided approaches spanning virtual screening, molecular networking, and deep learning have enabled identification of unconventional antibacterial scaffolds from ultra-large chemical libraries. Mining genomes, proteomes, and metagenomes has uncovered antimicrobial peptides, encrypted peptides, and biosynthetic gene clusters encoding novel small-molecule antibiotics. Generative AI now enables design of peptides and small molecules under multiobjective constraints, including potency, toxicity, stability, and resistance risk. Together, these advances point toward discovery platforms that improve novelty, hit rates, and long-term durability in the face of AMR.