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.
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Authors | John B Biggins, Melinda A Ternei, Sean F Brady |
Journal | Journal of the American Chemical Society
(J Am Chem Soc)
Vol. 134
Issue 32
Pg. 13192-5
(Aug 15 2012)
ISSN: 1520-5126 [Electronic] United States |
PMID | 22765305
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Lactones
- Virulence Factors
- malleilactone
- Polyketide Synthases
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Topics |
- Burkholderia pseudomallei
(enzymology, genetics)
- Cell Line
- Enzyme Activation
- Humans
- Inhibitory Concentration 50
- Lactones
(chemistry)
- Metabolome
- Models, Biological
- Multigene Family
- Polyketide Synthases
(genetics, metabolism)
- Promoter Regions, Genetic
- Virulence Factors
(genetics, metabolism)
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