Small molecules play important roles in both the establishment and propagation of bacterial infections. Although the characterization of small molecules produced by bacterial pathogens grown under controlled conditions in the laboratory has led to the discovery of many important signaling molecules and toxins, laboratory fermentation conditions are not representative of the growth conditions under which an infection occurs. Laboratory based fermentation studies are therefore unlikely to have provided access to the full repertoire of molecules used by bacterial pathogens during an infection. Cryptic small molecule biosynthetic gene clusters, gene clusters that do not appear to encode the biosynthesis of any known metabolites, are routinely found in sequenced bacterial genomes. These cryptic pathways represent the pool of pathways from which additional signaling systems and toxins will be found in bacterial pathogens. The work outlined in this proposal will provide access to previously unknown molecules encoded by the cryptic biosynthetic pathways found in the genomes of biodefense relevant bacterial pathogens. A detailed analysis of the genomes of many biodefense relevant pathogens suggests that they contain numerous previously unknown gene clusters that likely code for the biosynthesis of, as yet, unidentified small molecules. The genomics based approaches that we are using for the discovery of small molecules should result in a more complete description of the complex networks of small molecule signals and toxins that are used by biodefense relevant bacterial pathogens;and as a result, provide novel insights into how best to disrupt key steps in the establishment and propagation of bacterial infections.

Public Health Relevance

The work proposed here will provide access to novel small molecules encoded by the genomes of biodefense relevant bacterial pathogens. The characterization of new small molecule based signaling systems and new toxin biosynthetic pathways should provide novel insights into how best to manipulate biodefense relevant bacterial pathogens for the benefit of human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057158-07
Application #
8043566
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
7
Fiscal Year
2010
Total Cost
$822,680
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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