New Natural Product Antibiotics: Strategies and Tools That Offer New Approaches to Overcome Traditional Roadblocks

Microbial natural products have been the cornerstone of antibiotics used in medicine since their discovery in the early twentieth century. Shaped by natural selection, natural products are privileged compounds that often target complex biological systems. Despite this success, they have increasingly been abandoned by the drug discovery industry. A principal reason for moving away from natural products is the repeated identification of common antibiotic chemical scaffolds through traditional cell-killing phenotypic assays. However, synthetic compounds have largely failed to fill the antibiotic discovery gap. Advances in genomics, bioinformatics, and analytical chemistry have, in recent years, combined to show that there is still significant chemical diversity to be explored in microbes, providing an opportunity to revisit natural products for antibiotic discovery. Sourcing compounds from rare organisms through genome mining and rapid triage using metabolomics are being used to find new compounds with novel modes of action, opening the door to a new era in antibiotic innovation.