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 five 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 an analysis of the pathways that provide the building blocks for PQS and the characterization of novel regulatory systems that affect quinolone signaling. The completion of these studies will further our understanding of quinolone signaling and should provide a solid foundation on which to pursue future studies aimed at developing novel therapeutic treatments for P. aeruginosa.
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 understand the PQS signaling pathway and the factors which control it and factors which it controls. Future applications of our findings will hopefully lead to novel therapies designed to interfere with PQS signaling and thereby lessen the virulence of P. aeruginosa, making it more susceptible to known antibiotics and/or the host's immune response.
|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 :|
|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|
|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|