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J Am Chem Soc. 2012 Aug 15;134(32):13192-5. doi: 10.1021/ja3052156. Epub 2012 Aug 1.

Malleilactone, a polyketide synthase-derived virulence factor encoded by the cryptic secondary metabolome of Burkholderia pseudomallei group pathogens.

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1
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University and Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10068, USA.

Abstract

Sequenced bacterial genomes are routinely found to contain gene clusters that are predicted to encode metabolites not seen in fermentation-based studies. Pseudomallei group Burkholderia are emerging pathogens whose genomes are particularly rich in cryptic natural product biosynthetic gene clusters. We systematically probed the influence of the cryptic secondary metabolome on the virulence of these bacteria and found that disruption of the MAL gene cluster, which is natively silent in laboratory fermentation experiments and conserved across this group of pathogens, attenuates virulence in animal models. Using a promoter exchange strategy to activate the MAL cluster, we identified malleilactone, a polyketide synthase-derived cytotoxic siderophore encoded by this gene cluster. Small molecules targeting malleilactone biosynthesis either alone or in conjunction with antibiotics could prove useful as therapeutics to combat melioidosis and glanders.

PMID:
22765305
PMCID:
PMC3514402
DOI:
10.1021/ja3052156
[Indexed for MEDLINE]
Free PMC Article
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