Pseudomonas aeruginosa is an opportunistic pathogen that is a leading cause of nosocomial infections and lung infections in individuals with cystic fibrosis (CF). This ubiquitous bacterium adapts to its surroundings in many ways, one of which is to utilize small chemical compounds as signals for cell-to-cell communication. These signals control many cellular functions and are important in the infectious process. This proposal will focus on the quinolone signaling system, which utilizes the Pseudomonas Quinolone Signal (PQS;2-heptyl-3-hydroxy- 4-quinolone) as a coinducer for the transcriptional regulator PqsR. PqsR-PQS positively regulates quinolone production and numerous virulence factors required for infection. PQS is also produced in the lungs of infected CF patients, implying that quinolone signaling has a role in human disease. Our progress over the first four years of this proposal has led to the characterization of part of the PQS synthetic pathway and provided us with information on the regulation and synthesis of PQS, and on the activity exerted by PQS. Overall, the available data indicate that PQS signaling is a complicated and important part of P. aeruginosa cell-to-cell communication. Because of this, we propose experiments that will help to better understand PQS and its role in intercellular signaling. We plan to identify genes that are regulated by PqsR- PQS and to learn how pqsR is controlled. Our studies will also include the functional analysis of PqsE, an effector needed for PQS activity. We plan to continue to characterize the enzymes required for PQS synthesis in order to complete the mapping of the entire metabolic pathway. Finally, we will identify compounds that inhibit PQS synthetic enzymes and will test these compounds for the ability to inhibit virulence in a zebrafish model of P. aeruginosa infection. The completion of these studies will further our understanding of quinolone signaling and should provide a solid foundation to pursue future studies aimed at developing novel therapeutic treatments for P. aeruginosa.

Public Health Relevance

Pseudomonas aeruginosa is a major cause of hospital-acquired infections and also chronically infects the lungs of most individuals with cystic fibrosis This proposed research is aimed at understanding one of the cell-to-cell communication pathways used by this bacterium to control numerous cellular functions, including virulence. The long term goal of this research is to identify components of the PQS signaling pathway that will serve as targets for novel therapies designed to interfere with intercellular communication and thereby lessen the virulence of P. aeruginosa and make it more susceptible to known antibiotics and/or the host's immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI076272-06
Application #
8432926
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Taylor, Christopher E,
Project Start
2007-12-01
Project End
2017-12-31
Budget Start
2014-09-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
East Carolina University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Greenville
State
NC
Country
United States
Zip Code
27858
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
Ling, Elizabeth A; Ellison, Matthew L; Pesci, Everett C (2009) A novel plasmid for detection of N-acyl homoserine lactones. Plasmid 62:16-21

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