Metabologenomics-Driven Discovery of Nocardimicins from a Psychrophilic <i>Nocardia</i> sp. Strain

A combined strategy of 2D-NMR-metabolomics-driven substructure tracking with genome mining led to the targeted discovery of 10 nocobactin-type lipopeptides (<b>1</b>-<b>10</b>) from the Arctic-derived phychrophillic <i>Nocardia</i> sp. L-016, among which <b>1</b>-<b>5</b> are new compounds, named nocardimicins S-W. The phenoxazole moiety in <b>1</b>-<b>10</b>, featuring unique NMR values and correlations, was used as a probe for tracking nocardimicin analogues. The structures of <b>1</b>-<b>5</b> were established based on extensive MS and NMR spectroscopic analyses. The biosynthesis of nocardimicins (<b>1</b>-<b>10</b>) in <i>Nocardia</i> sp. L-016 is proposed to be achieved by the <i>noc</i> biosynthetic gene cluster, which is composed of two sub-gene clusters (I and II) separated by a 228 kb region. Compounds <b>1</b>-<b>10</b> showed moderate inhibition against human cancer cell lines of HCT116 and HepG2 with IC₅₀ values in the range of 3.5-10.2 μM. This work provides an effective application of paired-omics technologies in the discovery of new natural products.