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

Publikation: Beitrag in FachzeitschriftKurzmitteilungForschungPeer-Review

Autoren

  • Felix Trottmann
  • Jakob Franke
  • Ingrid Richter
  • Keishi Ishida
  • Michael Cyrulies
  • Hans Martin Dahse
  • Lars Regestein
  • Christian Hertweck

Externe Organisationen

  • Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V.Hans-Knöll-Institut
  • Friedrich-Schiller-Universität Jena
Forschungs-netzwerk anzeigen

Details

OriginalspracheEnglisch
Seiten (von - bis)14129-14133
Seitenumfang5
FachzeitschriftAngewandte Chemie - International Edition
Jahrgang58
Ausgabenummer40
Frühes Online-Datum28 Juli 2019
PublikationsstatusVeröffentlicht - 1 Okt. 2019

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.

ASJC Scopus Sachgebiete

Zitieren

Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human- and Animal-Pathogenic Burkholderia Species. / Trottmann, Felix; Franke, Jakob; Richter, Ingrid et al.
in: Angewandte Chemie - International Edition, Jahrgang 58, Nr. 40, 01.10.2019, S. 14129-14133.

Publikation: Beitrag in FachzeitschriftKurzmitteilungForschungPeer-Review

Trottmann F, Franke J, Richter I, Ishida K, Cyrulies M, Dahse HM et al. Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human- and Animal-Pathogenic Burkholderia Species. Angewandte Chemie - International Edition. 2019 Okt 1;58(40):14129-14133. Epub 2019 Jul 28. doi: 10.1002/anie.201907324, 10.1002/ange.201907324, 10.15488/9268
Trottmann, Felix ; Franke, Jakob ; Richter, Ingrid et al. / Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human- and Animal-Pathogenic Burkholderia Species. in: Angewandte Chemie - International Edition. 2019 ; Jahrgang 58, Nr. 40. S. 14129-14133.
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title = "Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human- and Animal-Pathogenic Burkholderia Species",
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.",
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note = "Funding Information: We thank A. Perner for LC-MS measurements and H. Heinecke for NMR measurements. Financial support by the DFG (SFB 1127 ChemBioSys, and Leibniz Award to C.H.), the European Regional Development Fund (ERDF) (MassNat), and the European Research Council (ERC) (MSCA-IF-EF-RI Project 794343 to I.R.) is gratefully acknowledged. J.F. acknowledges financial support by the SMART BIOTECS alliance between the Technische Universit{\"a}t Braunschweig and the Leibniz Universit{\"a}t Hannover, supported by the Ministry of Science and Culture (MWK) of Lower Saxony, Germany. ",
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AU - Trottmann, Felix

AU - Franke, Jakob

AU - Richter, Ingrid

AU - Ishida, Keishi

AU - Cyrulies, Michael

AU - Dahse, Hans Martin

AU - Regestein, Lars

AU - Hertweck, Christian

N1 - Funding Information: We thank A. Perner for LC-MS measurements and H. Heinecke for NMR measurements. Financial support by the DFG (SFB 1127 ChemBioSys, and Leibniz Award to C.H.), the European Regional Development Fund (ERDF) (MassNat), and the European Research Council (ERC) (MSCA-IF-EF-RI Project 794343 to I.R.) is gratefully acknowledged. J.F. acknowledges financial support by the SMART BIOTECS alliance between the Technische Universität Braunschweig and the Leibniz Universität Hannover, supported by the Ministry of Science and Culture (MWK) of Lower Saxony, Germany.

PY - 2019/10/1

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N2 - 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.

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