Genome-directed discovery of an octalin-containing polyether ionophore improves diabetic skin wound healing

Chronic hard-to-heal skin wounds in diabetes mellitus pose a significant clinical challenge, underscoring the urgent need for additional therapeutics. Herein, we report the identification of a polyether biosynthetic gene cluster (pdm BGC) from the marine-derived Streptomyces marincola SCSIO 03032 through genome mining. By overexpressing the positive regulator gene pdmRI, we increase the product of the pdm BGC 48-fold to enable the isolation, structural determination, and biosynthesis investigation of an octalin-containing polyether ionophore polydecalinmycin (PDM). Functionally, PDM demonstrates remarkable efficacy in promoting acute skin wound healing in BALB/c mice and significantly accelerating chronic wound closure in a diabetic mouse (db/db, male) model. Mechanistically, PDM induces an elevation of mitochondrial Na+ levels to trigger a transient burst of reactive oxygen species, a critical signal for initiating acute wound closure. Upon prolonged exposure, PDM activates a robust Nrf2-mediated antioxidant response, restoring mitochondrial homeostasis and conferring cytoprotection against high-glucose-induced oxidative stress. These insights highlight the therapeutic potential of PDM as a natural polyether candidate for developing ionophore-based strategies for diabetic wound healing. Chronic skin wounds in diabetes mellitus pose a clinical challenge that requires additional therapeutics. Here the authors report a polyether biosynthetic gene cluster, engineer a bioproduction platform for the ionophore polydecalinmycin, and demonstrate its wound healing abilities.