Abstract
Abstract Microorganisms are now recognized as a keysource of medicine. In this study, we aim to identify and characterize target-specific inhibitors from actinobacteria using zebrafish embryo developmental defect as readouts. From our preliminary screen, we evaluated 176 Malaysian actinobacteria extracts and from these, 15 extracts (8.52%) were observed to be toxic to embryos at 20 μg/mL at 72-h post fertilization (hpf). Detailed characterization of these 15 toxic hits uncovered one extract derived from Streptomyces californicus TY004-069 that arrested zebrafish embryonic development at 4–6 hpf after 24 h treatment, a phenotype indicative potentially targeting mitochondrial activity. Subsequent validation on one of the three isolated compounds from this extract, dimeric dinactin (DD) revealed its ability to disrupt mitochondrial membrane potential (MMP) in human colorectal HCT116 and HT29 cancer cells in a dose-dependent manner and impacting cell proliferation through a cell cycle G1 block. Overall, using zebrafish phenotypic assay, we identified a potential mitochondrial function inhibitor from actinobacteria that warrants further detailed analysis and also demonstrated that macrolides may hold promise as therapeutic molecules for human diseases including cancer.
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