2. Academic Validation
  3. Discovery and Biosynthesis of the Cytotoxic Polyene Terpenomycin in Human Pathogenic Nocardia

Discovery and Biosynthesis of the Cytotoxic Polyene Terpenomycin in Human Pathogenic Nocardia

  • ACS Chem Biol. 2023 Aug 18;18(8):1872-1879. doi: 10.1021/acschembio.3c00311.
Marion Herisse 1,  Keishi Ishida 2,  Jordan Staiger-Creed 1,  Louise Judd 1,  Spencer J Williams 3 4,  Benjamin P Howden 1 5,  Timothy P Stinear 1,  Hans-Martin Dahse 6,  Kerstin Voigt 7 8,  Christian Hertweck 2 9,  Sacha J Pidot 1
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3000, Australia.
  • 2 Department of Biomolecular Chemistry, Leibniz Institute, for Natural Product Chemistry and Infection Biology (HKI), Beutenbergstrasse 11a, Jena 07745, Germany.
  • 3 School of Chemistry, University of Melbourne, Melbourne, Victoria 3000, Australia.
  • 4 Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3000, Australia.
  • 5 Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria3000, Australia.
  • 6 Department of Infection Biology, Leibniz Institute, for Natural Product Chemistry and Infection Biology (HKI), Beutenbergstrasse 11a, Jena 07745, Germany.
  • 7 Jena Microbial Resource Collection, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstrasse 11a, Jena 07745, Germany.
  • 8 Institute of Microbiology, Friedrich Schiller University Jena, 07743 Jena, Germany.
  • 9 Natural Product Chemistry, Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena 07743, Germany.
PMID: 37498707 DOI: 10.1021/acschembio.3c00311
Abstract

Nocardia are opportunistic human pathogens that can cause a range of debilitating and difficult to treat infections of the lungs, brain, skin, and soft tissues. Despite their close relationship to the well-known secondary metabolite-producing genus, Streptomyces, comparatively few Natural Products are known from the Nocardia, and even less is known about their involvement in the pathogenesis. Here, we combine chemistry, genomics, and molecular microbiology to reveal the production of terpenomycin, a new cytotoxic and Antifungal polyene from a human pathogenic Nocardia terpenica isolate. We unveil the polyketide synthase (PKS) responsible for terpenomycin biosynthesis and show that it combines several unusual features, including "split", skipped, and iteratively used modules, and the use of the unusual extender unit methoxymalonate as a starter unit. To link genes to molecules, we constructed a transposon mutant library in N. terpenica, identifying a terpenomycin-null mutant with an inactivated terpenomycin PKS. Our findings show that the neglected actinomycetes have an unappreciated capacity for the production of bioactive molecules with unique biosynthetic pathways waiting to be uncovered and highlights these organisms as producers of diverse Natural Products.

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