Molecular landscape analysis of azinothricin-type natural products enables the identification of kettapeptin from Streptomyces durmitorensis

The azinothricin family of hybrid hexadepsipeptide-polyketide natural products exhibit remarkable bioactivities, including potent antibacterial, antitumor, antimalarial and anti-inflammatory activities. However, only a few azinothricin-type natural products are currently known, and the biosynthetic potential of microbes remains underexplored. In this work, 137 candidate biosynthetic gene clusters (BGCs) were identified using a genome-mining strategy based on cblaster homology screening. Furthermore, <i>Streptomyces durmitorensis</i> DSM 41863 was prioritized for in-depth experiment due to its unique PKS module expansion, leading to the discovery of kettapeptin, the azinothricin-type metabolite isolated from this species for the first time. Additionally, a putative biosynthetic pathway for kettapeptin was proposed. This work expands the azinothricin-type BGC landscape and establishes <i>S</i>. <i>durmitorensis</i> DSM 41863 as a genetically tractable platform for bioengineering novel derivatives.