Pseudomonas aeruginosa is responsible for approximately 10% of the hospital-acquired infections in the U.S., and causes a chronic, debilitating lung infection in most cystic fibrosis patients. Adding to the significance of these infections is the fact that this organism is capable of rapidly developing resistance to many antibiotics, which significantly limits treatment options. While the need for novel antimicrobial treatments has been pressing for years, the development of useful new antibiotics has been difficult. One promising line of research has centered on the cell-to-cell signaling systems used by bacteria to control many functions, including virulence. P. aeruginosa uses three different intercellular signaling systems to coordinate gene expression and the topic of this proposal is the signal 2-heptyl-3-hydroxy-4-quinolone [referred to as the Pseudomonas Quinolone Signal (PQS)]. PQS is required for virulence in plants, insects, and animals and is produced in the lungs of cystic fibrosis patients who are infected by P. aeruginosa. Our plan is to complete experiments that will help us to better understand the significance of PQS in P. aeruginosa cell-to-cell signaling and virulence. We propose focused experiments that will address how PQS activates genes, and the mechanisms behind its synthesis. The long term goal of this research is to develop methods that interfere with PQS signaling. We believe that the PQS signaling system and the components required for its proper function will provide targets at which to aim future therapeutic interventions that will decrease P. aeruginosa virulence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076272-05
Application #
8197168
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Taylor, Christopher E,
Project Start
2007-12-01
Project End
2013-12-31
Budget Start
2011-12-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$316,451
Indirect Cost
$95,928
Name
East Carolina University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Cole, Stephanie J; Hall, Cherisse L; Schniederberend, Maren et al. (2018) Host suppression of quorum sensing during catheter-associated urinary tract infections. Nat Commun 9:4436
Farrow 3rd, John M; Pesci, Everett C (2017) Distal and proximal promoters co-regulate pqsR expression in Pseudomonas aeruginosa. Mol Microbiol 104:78-91
Ji, Cheng; Sharma, Indrajeet; Pratihar, Debarshi et al. (2016) Designed Small-Molecule Inhibitors of the Anthranilyl-CoA Synthetase PqsA Block Quinolone Biosynthesis in Pseudomonas aeruginosa. ACS Chem Biol 11:3061-3067
Tipton, Kyle A; Coleman, James P; Pesci, Everett C (2015) Post-transcriptional regulation of gene PA5507 controls Pseudomonas quinolone signal concentration in P.?aeruginosa. Mol Microbiol 96:670-83
Lidor, O; Al-Quntar, A; Pesci, E C et al. (2015) Mechanistic analysis of a synthetic inhibitor of the Pseudomonas aeruginosa LasI quorum-sensing signal synthase. Sci Rep 5:16569
Farrow 3rd, John M; Hudson, L Lynn; Wells, Greg et al. (2015) CysB Negatively Affects the Transcription of pqsR and Pseudomonas Quinolone Signal Production in Pseudomonas aeruginosa. J Bacteriol 197:1988-2002
Knoten, Claire A; Wells, Greg; Coleman, James P et al. (2014) A conserved suppressor mutation in a tryptophan auxotroph results in dysregulation of Pseudomonas quinolone signal synthesis. J Bacteriol 196:2413-22
Tipton, Kyle A; Coleman, James P; Pesci, Everett C (2013) QapR (PA5506) represses an operon that negatively affects the Pseudomonas quinolone signal in Pseudomonas aeruginosa. J Bacteriol 195:3433-41
Ellison, Matthew L; Farrow 3rd, John M; Farrow 4th, John Matthew et al. (2013) The transcriptional regulator Np20 is the zinc uptake regulator in Pseudomonas aeruginosa. PLoS One 8:e75389
Knoten, Claire A; Hudson, L Lynn; Coleman, James P et al. (2011) KynR, a Lrp/AsnC-type transcriptional regulator, directly controls the kynurenine pathway in Pseudomonas aeruginosa. J Bacteriol 193:6567-75

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