GENOMICS-BASED DISCOVERY AND ANTICANCER ACTIVITY ASSESSMENT OF NEW THIOVIRIDAMIDE-LIKE MOLECULES PRODUCED BY ACTINOBACTERIA

Thioviridamide is a ribosomally synthesized and post translationally modified peptide (RiPP) produced by Streptomyces olivoviridis NA005001. This microbial secondary metabolite is characterized by an unusual structure including several thioamide groups, which represent a rare feature among bacterial peptides, and it is endowed with a strong anti-proliferative activity, highly selective towards cancer cells.(1) These features led us to investigate the diversity of thioviridamidelike pathways across sequenced bacterial genomes. A genomics-based approach allowed us to identify, isolate and structurally characterize three new thioviridamide-like molecules (TLMs), whose structural variability was found to reflect the diversity of biosynthetic pathways.(2) Gene cluster disruption in producer strain and its heterologous expression in a host strain (Streptomyces coelicolor M1146) allowed us to confirm the correlation between the gene clusters and the new identified compounds. Among the new TLMs, thioalbamide was tested for its anticancer properties. This new natural product displayed anti-proliferative activity on several cancer cell lines, even when used at nanomolar concentrations. Our outcomes also provide new insights on the underlying mechanism of such effect, highlighting thioalbamide’s ability to induce metabolic dysfunction, oxidative stress and apoptotic cell death. Our findings are confirmed by the evidence that thioalbamide is able to inhibit the propagation of cancer stem-like cells, which is strongly dependent on mitochondrial function and is responsible for chemotherapy resistance, metastasis and tumor recurrence. Our results provide new insights into TLMs biological effects, as well as they open new scenarios for the application of this rare class of microbial thioamidated peptides in oncologic field.