Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706.
Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853.
Proc Natl Acad Sci U S A. 2021 Feb 23;118(8). doi: 10.1073/pnas.2015224118.
The maintenance of sufficient but nontoxic pools of metal micronutrients is accomplished through diverse homeostasis mechanisms in fungi. Siderophores play a well established role for iron homeostasis; however, no copper-binding analogs have been found in fungi. Here we demonstrate that, in , xanthocillin and other isocyanides derived from the biosynthetic gene cluster (BGC) bind copper, impact cellular copper content, and have significant metal-dependent antimicrobial properties. BGC-derived isocyanides are secreted and bind copper as visualized by a chrome azurol S (CAS) assay, and inductively coupled plasma mass spectrometry analysis of intracellular copper pools demonstrated a role for cluster metabolites in the accumulation of copper. coculture with a variety of human pathogenic fungi and bacteria established copper-dependent antimicrobial properties of BGC metabolites, including inhibition of laccase activity. Remediation of xanthocillin-treated growth by copper supported the copper-chelating properties of BGC isocyanide products. The existence of the BGC in several filamentous fungi suggests a heretofore unknown role of eukaryotic natural products in copper homeostasis and mediation of interactions with competing microbes.
真菌通过多种体内平衡机制来维持充足但无毒的金属微量元素池。铁载体在铁体内平衡中起着重要作用；然而，在真菌中尚未发现铜结合类似物。在这里，我们证明了，在，黄杉素和其他异氰化物衍生自生物合成基因簇（BGC）结合铜，影响细胞内铜含量，并具有显著的金属依赖性抗菌特性。BGC 衍生的异氰化物被分泌出来，并通过铬天青 S（CAS）测定法可视化结合铜，细胞内铜池的电感耦合等离子体质谱分析表明 BGC 代谢物在铜积累中起作用。与各种人类致病真菌和细菌的共培养建立了 BGC 代谢物的铜依赖性抗菌特性，包括抑制漆酶活性。铜支持 BGC 异氰化物产物的铜螯合特性，修复了黄杉素处理后的生长。几种丝状真菌中存在 BGC 表明真核天然产物在铜体内平衡和与竞争微生物相互作用的调节中具有未知的作用。
