Copper is a transition metal element with significant effects on the morphological development and secondary metabolism of actinobacteria. In some microorganisms, copper-binding natural products are employed to modulate copper homeostasis, although their significance in actinobacteria remains largely unknown. Here, we identified the biosynthetic genes of the diisocyanide natural product hazimycin in Kitasatospora purpeofusca HV058, through gene knock-out and heterologous expression. Biochemical analyses revealed that hazimycin A specifically binds to copper, which diminishes its antimicrobial activity. The presence of a set of putative importer/exporter genes surrounding the biosynthetic genes suggested that hazimycin is a chalkophore that modulates the intracellular copper level. A bioinformatic survey of homologous gene cassettes, as well as the identification of two previously unknown hazimycin-producing Streptomyces strains, indicated that the isocyanide-based mechanism of copper homeostasis is prevalent in actinobacteria.

铜是一种过渡金属元素，对放线菌的形态发育和次生代谢具有显着影响。在一些微生物中，铜结合天然产物被用来调节铜稳态，尽管它们在放线菌中的重要性仍然很大程度上未知。在这里，我们通过基因敲除和异源表达，鉴定了Kitasatospora purpeofusca HV058中二异氰化物天然产物哈齐霉素的生物合成基因。生化分析表明，hazimycin A 与铜特异性结合，从而降低了其抗菌活性。围绕生物合成基因的一组假定的输入/输出基因的存在表明哈齐霉素是调节细胞内铜水平的白垩基团。对同源基因盒的生物信息学调查以及两种以前未知的产生哈齐霉素的链霉菌菌株的鉴定表明，基于异氰化物的铜稳态机制在放线菌中普遍存在。