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

Herein, we report the identification of a new polyether biosynthetic gene cluster (pdm BGC) from the marine-derived Streptomyces marincola SCSIO 03032 through genome mining. The product of the pdm BGC was increased 48-fold by overexpression of the positive regulator gene pdmRI in this BGC to direct the isolation, structural determination, and biosynthesis analysis of a unique octalin-containing polyether ionophore polydecalinmycin (PDM).

Further bioactivity investigations identified PDM as a dual sodium (Na+) ionophore and protonophore. This dual functionality induces a moderate mitochondrial Na+ and H+ leak, thereby enhancing the generation of reactive oxygen species and ameliorating mitochondrial energy metabolism. This novel and comprehensive strategy endows PDM with versatile effects on cells involved in wound healing, facilitating key healing processes such as proliferation, migration, and angiogenesis.