Genome-directed discovery of antiproliferative bafilomycins from a deepsea-derived Streptomyces samsunensis

Genomic bioinformatics analysis identified a bafilomycin biosynthetic gene cluster (named bfl ) in the deepsea-derived S. samsunensis OUCT16-12, from which two new ( 1 and 2, named bafilomycins R and S) along with four known ( 3 – 6 ) bafilomycins were targetly obtained. The structure of 3 was clearly identified for the first time, thus named bafilomycin T herein. Differ from the fumarate substitution at C-21 of known bafilomycins, its location on C-23 is a unique feature of 1 and 2. The stereochemistry of the compounds was established based on NOE correlations, ketoreductase (KR)-types in PKS modules of bfl, and ECD calculations. Moreover, a detailed biosynthetic model of 1 – 6 in S. samsunensis OUCT16-12 was provided based on the gene function prediction and sequence identity. Compared with the positive control doxorubicin, 1 – 6 showed more potent antiproliferative activities against drug-resistant lung cancer cell line A549-Taxol, with IC 50 values ranging from 0.07 μM to 1.79 μM, which arrested cell cycle in G0/G1 phase to hinder proliferation.