Metabologenomic Hallmark‐Based Discovery of Bacterial Thioamides as a New Lead against Drug‐Resistant Pancreatic Cancer

Thioamides constitute an important class of pharmaceutically active natural products, yet their discovery and development are limited. A targeted metabologenomic method is developed to logically and efficiently discover thioamide compounds in bacteria. To this end, two strains were identified to possess genetic capacity for biosynthesizing thioamides from the bacterial genomic DNA library (1,192 strains) using the polymerase chain reaction to target the TfuA-encoding gene, a genomic hallmark of thioamide biosynthesis. Mass spectrometric isotopic patterns of sulfur-bearing compounds serve as metabolomic hallmarks to detect thioamide production from the extracts of the selected strains without chromatography. Applying this metabologenomic targeting approach, two new thioamides, thiogochangamides A and B, belonging to the thioviridamide family whose stereochemistry has remained unresolved for two decades, were discovered in Streptomyces sp. Their absolute configurations were fully assigned through chemical derivatizations, including the advanced Marfey method, Mosher method, partial hydrolysis, synthesis of an unusual amino acid, and desulfurization, combined with computational methods. Thiogochangamide B exhibits potent inhibitory activity against gemcitabine-resistant pancreatic cancer cells both in vitro and in vivo. Mechanistically, thiogochangamide B effectively downregulates Wnt/β-catenin signaling, thereby suppressing the metastatic potential of drug-resistant cancer cells. This study provides a new therapeutic strategy for overcoming recalcitrant drug-resistant pancreatic cancer.