Details
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 14129-14133 |
| Seitenumfang | 5 |
| Fachzeitschrift | Angewandte Chemie - International Edition |
| Jahrgang | 58 |
| Ausgabenummer | 40 |
| Frühes Online-Datum | 28 Juli 2019 |
| Publikationsstatus | Veröffentlicht - 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
- Chemische Verfahrenstechnik (insg.)
- Katalyse
- Chemie (insg.)
- Allgemeine Chemie
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in: Angewandte Chemie - International Edition, Jahrgang 58, Nr. 40, 01.10.2019, S. 14129-14133.
Publikation: Beitrag in Fachzeitschrift › Kurzmitteilung › Forschung › Peer-Review
}
TY - JOUR
T1 - Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human- and Animal-Pathogenic Burkholderia Species
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
Y1 - 2019/10/1
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.
AB - 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.
KW - mass spectrometry
KW - natural products
KW - polyketides
KW - structure elucidation
KW - virulence factors
UR - http://www.scopus.com/inward/record.url?scp=85071265811&partnerID=8YFLogxK
U2 - 10.1002/anie.201907324
DO - 10.1002/anie.201907324
M3 - Short/Brief/Rapid Communication
C2 - 31353766
AN - SCOPUS:85071265811
VL - 58
SP - 14129
EP - 14133
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1433-7851
IS - 40
ER -