Undescribed polyether ionophores from Streptomyces cacaoi and their antibacterial and antiproliferative activities

Polyether ionophores represent a large group of naturally occurring compounds mainly produced by Streptomyces species. With previously proven varieties of bioactivity including antibacterial, antifungal, antiparasitic, antiviral and anti-tumor effects, the discovery of undescribed polyethers leading to development of efficient therapeutics has become important. As part of our research on polyether-rich Streptomyces cacaoi, we previously performed modification studies on fermentation conditions to induce synthesis of specialized metabolites. Here, we report four undescribed and nine known polyether compounds from S. cacaoi grown in optimized conditions. Antimicrobial activity assays revealed that four compounds, including the undescribed (6), showed strong inhibitory effects over both Bacillus subtilis and methicillin-resistant Staphylococcus aureus (MRSA) growth. Additionally, K41-A and its C15-demethoxy derivative exhibited significant cytotoxicity. These results signified that selectivity of C15-demethoxy K41-A towards cancer cells was higher than K41-A, which prompted us to conduct mechanistic experiments. These studies showed that this uninvestigated compound acts as a multitarget compound by inhibiting autophagic flux, inducing reactive oxygen species formation, abolishing proteasome activity, and stimulating ER stress. Consequently, the optimized fermentation conditions of S. cacaoi led to the isolation of undescribed and known polyethers displaying promising activities. Thirteen polyether compounds were isolated from S. cacaoi grown in optimized conditions and their antibacterial, and cytotoxic activities were evaluated. [Display omitted] •Four undescribed and nine known polyether compounds were isolated from S. cacaoi.•Growth inhibitory effects over bacteria and cancer cells were observed.•Amicetose moiety and O-methylation on the ring A are important for bioactivities.•Compound 4 showed selective cytotoxicity against cancer cells.•Compound 4 inhibited autophagy as well as induced UPR and ROS production.