Overexpression of Global Regulator ShCrp Leads to the Discovery of Polycyclic Tetramate Macrolactams in Streptomyces hebeiensis HDN10-293

Two new polycyclic tetramate macrolactams (PTMs), shebamides A and B ( 1 and 2 ), were isolated from Streptomyces hebeiensis HDN10-293 following the activation of cryptic biosynthetic gene clusters by overexpression of the global regulator Crp. Their structures were elucidated via comprehensive spectroscopic analysis and electronic circular dichroism calculations, revealing a C-30 ketone─an oxidative modification rarely observed in the PTMs. Compound 1 exhibited significant cytotoxicity against 4 human cancer cell lines (IC 50 6.45–12.30 μM). Their biosynthetic pathway was further proposed through functional gene cluster comparison. This study underscores the efficacy of global regulation-based genome mining for discovering structurally unique metabolites.