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Actinobacterial chalkophores: the biosynthesis of hazimycins

The Journal of Antibiotics volume 77, pages 228–237 (2024)Cite this article

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Abstract

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.

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Data availability

Genome sequence of K. purpeofusca HV058 was deposited in DDBJ under following accession ID: AP028455 (chromosome) and AP028456 (plasmid).

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Acknowledgements

This work was partly supported by Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), funded by MEXT under “Support Program for Implementation of New Equipment Sharing System”, Global Station for Biosurfaces and Drug Discovery, a project of Global Institution for Collaborative Research and Education in Hokkaido University, the Asahi Glass Foundation, the Naito Foundation, the Uehara Memorial Foundation, the Sumitomo Foundation−Grant for Basic Science Research Projects, Daiichi Sankyo Foundation of Life Science, Japan Foundation for Applied Enzymology, TERUMO Life Science Foundation, the Japan Agency for Medical Research and Development (AMED Grant Numbers JP23ak0101163, JP23ama121039, JP23gm1610007), Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Japan Science and Technology Agency (JST Grant Numbers ACT-X JPMJAX201F and A-STEP JPMJTR20US), JSPS KAKENHI (Grant numbers JP16H06448, JP18H02581, JP19K16390, JP21H02635, JP22K15302, JP22H05128 and JP23K17410).

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  1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, 060-0812, Japan

    Kenichi Matsuda, Hiroto Maruyama, Kumiko Imachi & Toshiyuki Wakimoto

  2. Technology Research Association for Next generation natural products chemistry, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan

    Haruo Ikeda

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Correspondence to Kenichi Matsuda or Toshiyuki Wakimoto.

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Matsuda, K., Maruyama, H., Imachi, K. et al. Actinobacterial chalkophores: the biosynthesis of hazimycins. J Antibiot 77, 228–237 (2024). https://doi.org/10.1038/s41429-024-00706-6

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