NMR-Metabologenomics Coupled with Activity-Picking Inspires Discovery of Samsumycins: a Fast-Mining Strategy for Novel Antibiotics.

The time-consuming and repetitive rediscovery of known molecules has long hindered the efficient identification of novel drug leads from natural sources. Metabologenomics, the synergistic integration of metabolomics and genomics, has emerged as a powerful strategy to circumvent these challenges, enabling targeted discovery of new chemical entities. In this study, we developed a 2D-NMR-based metabologenomics workflow integrated with high-throughput activity screening to rapidly identify a novel family of antibiotic macrolides, samsumycins (1-6), from the deep-sea Streptomyces sp. OUCT16-12. The planar and stereochemical structures of these compounds were elucidated through comprehensive spectroscopic analysis and NOE-constrained quantum chemical calculations. Remarkably, 2-6 feature an unprecedented 6/6/26-fused macrolide scaffold, biosynthesized via the hex gene cluster and subsequent late-stage Diels-Alder reactions. Among the analogues, 1 demonstrated the most potent antibacterial activity against multidrug-resistant (MDR) pathogens that were comparable to the positive control vancomycin. This work not only unveils the samsumycins as a structurally unique antibiotic family, detailing their discovery to biosynthetic logic, but also establishes an innovative, streamlined strategy for fast-mining of novel natural products in microbes.