Microbial-derived natural products provide the foundation for most of the chemotherapeutic arsenal available to contemporary medicine. In the face of a dwindling pipeline of new lead structures identified by traditional culturing techniques and an increasing need for new therapeutics, surveys of microbial biosynthetic diversity across environmental metabiomes have revealed enormous reservoirs of as yet untapped natural products chemistry. In this review, we touch on the historical context of microbial natural product discovery and discuss innovations and technological advances that are facilitating culture-dependent and culture-independent access to new chemistry from environmental microbiomes with the goal of reinvigorating the small molecule therapeutics discovery pipeline. We highlight the successful strategies that have emerged and some of the challenges that must be overcome to enable the development of high-throughput methods for natural product discovery from complex microbial communities.
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