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Angew Chem Int Ed Engl. 2019 Oct 1;58(40):14129-14133. doi: 10.1002/anie.201907324. Epub 2019 Aug 27.

Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human- and Animal-Pathogenic Burkholderia Species.

Author information

1
Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745, Jena, Germany.
2
Institute of Organic Chemistry, BMWZ, Leibniz University Hannover, 30167, Hannover, Germany.
3
Department Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology (HKI), 07745, Jena, Germany.
4
Department Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), 07745, Jena, Germany.
5
Natural Product Chemistry, Faculty of Biological Sciences, Friedrich Schiller University Jena, 07743, Jena, Germany.

Abstract

Burkholderia species such as B. mallei and B. pseudomallei are bacterial pathogens causing fatal infections in humans and animals (glanders and melioidosis), yet knowledge on their virulence factors is limited. While pathogenic effects have been linked to a highly conserved gene locus (bur/mal) in the B. mallei group, the metabolite associated to the encoded polyketide synthase, burkholderic acid (syn. malleilactone), could not explain the observed phenotypes. By metabolic profiling and molecular network analyses of the model organism B. thailandensis, the primary products of the cryptic pathway were identified as unusual cyclopropanol-substituted polyketides. First, sulfomalleicyprols were identified as inactive precursors of burkholderic acid. Furthermore, a highly reactive upstream metabolite, malleicyprol, was discovered and obtained in two stabilized forms. Cell-based assays and a nematode infection model showed that the rare natural product confers cytotoxicity and virulence.

KEYWORDS:

mass spectrometry; natural products; polyketides; structure elucidation; virulence factors

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