Antitubercular Ilamycins from Marine-Derived Streptomyces atratus SCSIO ZH16 ΔilaR

Tuberculosis (TB) ranks as the leading cause of death from a single infectious agent (ranking more lethal than HIV/AIDS) over the course of the past decade. More concerning is that reports of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB have been dramatically increasing. It continues to become ever more clear that novel anti-TB drugs with improved efficacies and reduced toxicities are urgently needed. We report here the discovery of 12 new ilamycin analogues, ilamycins G-R (1-12), bearing various nonproteinogenic amino acids, along with ilamycins E-1 (13) and F (14), from a 200 L scale culture of the marine-derived mutant actinomycete Streptomyces atratus SCSIO ZH16 Delta ilaR. Importantly, bioassays against Mycobacterium tuberculosis H37Rv revealed that all 12 new agents displayed antitubercular activities with MIC values ranging from 0.0096 to 10 mu M. The structures of 1-12 were elucidated on the basis of HRESIMS, 1D and 2D NMR, and X-ray single-crystal diffraction studies. In addition, compound 10 was found to be moderately cytotoxic against a panel of tumor human cell lines. From these data we can formulate tentative structure-activity relationships for the antitubercular and antitumor activities of the ilamycins.