Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human‐ and Animal‐Pathogenic Burkholderia Species. Issue 40 (27th August 2019)

• Record Type: Journal Article
• Authors: Trottmann, Felix; Franke, Jakob; Richter, Ingrid; Ishida, Keishi; Cyrulies, Michael; Dahse, Hans‐Martin; Regestein, Lars; Hertweck, Christian
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 40(2019)
• Page Start: 14129
• Page End: 14133
• Publication Date: 2019-08-27
• Subjects: natural products -- mass spectrometry -- polyketides -- structure elucidation -- virulence factors; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201907324
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : Virulence factor : The true effector molecules of a disease‐determining biosynthetic gene cluster from diverse pathogenic bacteria were discovered. Polyketides equipped with a cyclopropanol warhead show high chemical reactivity and strong potency in a eukaryotic infection model Caenorhabditis elegans . The chemical relationships between all the complex polyketides were decrypted.