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

Nicholas Raffa, Tae Hyung Won, Andrew Sukowaty, Kathleen Candor, Chengsen Cui, Saayak Halder, Mingji Dai, Julio A. Landero-Figueroa, Frank C. Schroeder, Nancy P. Keller

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

The maintenance of sufficient but nontoxic pools of metal micro-nutrients 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 Aspergillus fumigatus, xanthocillin and other isocyanides derived from the xan biosynthetic gene cluster (BGC) bind copper, impact cellular copper content, and have significant metal-dependent antimicrobial properties. xan 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 A. fumigatus intracellular copper pools demonstrated a role for xan cluster metabolites in the accumulation of copper. A. fumigatus coculture with a variety of human pathogenic fungi and bacteria established copper-dependent antimicrobial properties of xan BGC metabolites, including inhibition of laccase activity. Remediation of xanthocillin-treated Pseudomonas aeruginosa growth by copper supported the copper-chelating properties of xan BGC isocyanide products. The existence of the xan BGC in several filamentous fungi suggests a heretofore unknown role of eukaryotic natural products in copper homeostasis and mediation of interactions with competing microbes.

Original languageEnglish
Article numbere2015224118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number8
DOIs
StatePublished - 23 Feb 2021
Externally publishedYes

Keywords

  • Aspergillus
  • Chalkophore
  • Copper
  • Fungi
  • Isocyanide

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