Phenolmacrolide A, a Benzenoid Ansamycin from Marine-Derived Streptomyces olivaceus NBUA17 with In Vitro Antipancreatic Cancer Activity, Targets EEF1A2.

Ansamycins with diverse ring systems play an indispensable role in the pharmaceutical industry. A novel 20-membered ester-incorporating benzenoid ansamycin, phenolmacrolide A (1), and a new naphthalenoid ansamycin, olimycin I (2), were obtained from the marine-derived Streptomyces olivaceus NBUA17 using a strategy of combining genome mining, SNAP-MS, and HSQC NMR interpretation tools. Furthermore, investigation of the putative ansamycin biosynthetic gene cluster suggested that the novel benzenoid ansamycin scaffold of compound 1 could be formed in part by a hydroxylase and luciferase-like monooxygenase. Compound 1 exhibited moderate activity inhibiting proliferation, migration, and invasion against PANC-1 cells in vitro by inducing cell apoptosis and promoting cancer cell entry into G2/M phase, and inhibiting epithelial-mesenchymal transition. Further drug affinity-responsive target stability assay, molecular docking, cell thermal shift assay, and siRNA transfection identified EEF1A2 as a molecular target of compound 1 in PANC-1 cells. This study identifies an unprecedented subtype within the benzenoid ansamycin family, broadens the structural and bioactive diversity of macrocyclic ansamycins, and underscores the potential of marine-derived actinomycetes as a prolific source of pharmacologically promising lead molecules.