Dual-purpose isocyanides produced by contribute to cellular copper sufficiency and exhibit antimicrobial activity.

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.