Bacteria communicate with each other via a system of signals known as quorum sensing. In recent years it has been demonstrated that this complex system of communication can include not just bacterial produced signals, but also host derived signals to control gene expression of virulence in pathogenic species. This proposal combines the expertise of five laboratories to develop compounds that compromise bacterial quorum sensing. By targeting quorum sensing we decrease the possibility of the development of resistance as it is not an essential biological process and thus negative selective pressure will be minor. We have identified a promising compound that inhibits the virulence of enterohemorrhagic E. coli and Salmonella species causing numerous food poisoning syndromes, as well as Francisella tularensis, the causative agent of tularemia by interfering with quorum sensing. These three diverse organisms, and potentially many others, can all be targeted by a single compound due to the presence of a widely conserved membrane bound receptor protein. Preliminary data suggests that this compound is specific for bacterial systems at concentrations in the picomolar range and has no obvious adverse effects on the host. In addition to the single compound that we have significant preliminary data for a number of alternative distinct compounds have also been identified and may be further developed. Our consortium contains the expertise to rationally develop this or an alternative compound into effective broad-spectrum inhibitor of virulence rendering the bacteria harmless.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI077853-05
Application #
8294776
Study Section
Special Emphasis Panel (ZAI1-TP-M (J1))
Program Officer
Baqar, Shahida
Project Start
2008-06-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$1,075,870
Indirect Cost
$302,770
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Lu, Biao; Falck, John R (2008) Efficient iridium-catalyzed C-H functionalization/silylation of heteroarenes. Angew Chem Int Ed Engl 47:7508-10

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