Antimicrobial discovery from underexplored environments: unlocking specialized metabolism

The discovery of antibiotics transformed modern medicine and extended the average human lifespan by decades. However, the initial golden era of antibiotic discovery has significantly waned, a decline aggravated by the relentless evolution of drug resistance among human pathogens, ultimately driving the current global antimicrobial resistance (AMR) crisis. The repeated rediscovery of known compounds from conventional soil-derived microbes underscores the urgent need for new strategies and ecological frontiers.Here, we review emerging directions in antibiotic discovery that collectively address this innovation gap. Refined cultivation techniques such as co-culture and iChip have reactivated rare taxa and yielded novel scaffolds like teixobactin. Multi-omics and synthetic biology approaches now enable culture-independent access to cryptic biosynthetic gene clusters from the vast uncultivated microbial majority. Most recently, artificial intelligence (AI) has expanded the search frontier to neglected taxa such as archaea and even evolutionary timeframes through paleoproteome mining. Overall, these innovations signal a new era of intelligent, data-driven antibiotic discovery. The integration of ecology, omics, synthetic biology, and AI provides a sustainable framework to replenish the antibiotic pipeline and mitigate the growing threat of AMR.