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Cyclopropanol Warhead in Malleicyprol Confers Virulence of Human‐ and Animal‐Pathogenic Burkholderia Species
Author(s) -
Trottmann Felix,
Franke Jakob,
Richter Ingrid,
Ishida Keishi,
Cyrulies Michael,
Dahse HansMartin,
Regestein Lars,
Hertweck Christian
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201907324
Subject(s) - virulence , biology , microbiology and biotechnology , burkholderia pseudomallei , gene , burkholderia , polyketide synthase , polyketide , bacteria , genetics , biosynthesis
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.