The bacterium Pseudomonas aeruginosa is a common opportunistic human pathogen that causes life- threatening illnesses, including acute pneumonia, long-term lung colonization in most cystic fibrosis patients, and severe wound infections, especially in hospitalized patients and those with severe burns. Most P. aeruginosa infections are associated with compromised host defense and this, together with the common environmental occurrence of the organism, makes it the second most common cause of sepsis in the intensive care unit. The resolution of P. aeruginosa disease is challenging, in part because of its intrinsic resistance to antibiotics as well as occasional outbreaks of multi-drug-resistant strains in hospitals. Therefore, there is an urgent need to identify new targets for therapeutic attack. One of the most critical systems that P. aeruginosa uses to establish an infection is a complex protein export machine known as a type 3 secretion system. We have now discovered that inactivation of the uncharacterized P. aeruginosa gene PA5134/ctpA (periplasmic C- terminal processing protease) prevents normal type 3 secretion system activity, reduces the cytotoxicity of P. aeruginosa towards cultured mammalian cells, and severely attenuates it in an animal model of acute infection. However, we do not understand why. This exploratory project is founded on the central hypothesis that the cleavage of one or more cell envelope proteins by CtpA is required for normal type 3 secretion system activity. To test this hypothesis we will: (1) Identify substrates of CtpA and (2) Investigate the mechanism by which CtpA-dependent proteolysis affects type 3 secretion. This will provide critical insight into the roe of CtpA and a better understanding of how it affects Pa virulence. Such insight into the consequences of CtpA activity is very important, especially because this relatively accessible periplasmic protein could eventually be considered as an attractive target for therapeutic drugs that inactivate it.
The bacterium Pseudomonas aeruginosa is the cause of many serious human infections, particularly in hospitalized patients and/or those with weak immune systems. The proposed research has the potential to characterize a novel P. aeruginosa protein that must function normally during an acute infection. In the long- term, this molecule could perhaps be a target for the design of new therapeutic strategies against this devastating pathogen.
|Srivastava, Disha; Seo, Jin; Rimal, Binayak et al. (2018) A Proteolytic Complex Targets Multiple Cell Wall Hydrolases in Pseudomonas aeruginosa. MBio 9:|