Bacterial quorum sensing involves small molecule cell-cell siganling that allows coordination of behavior among individual cells in a population. Quorum sensing in the NIAID Category B Priority Pathogen Burkholderia mallei holds a particular interest. First, like for certain other pathogens such as Pseudomonas aeruginosa quorum sensing is involved in virulence of B. mallei. Efforts to develop anti-Pseudomonas quorum sensing inhibitors have been hindered by the lack of adequate animal models for Pseud0monas infections. The availability of such models for B. mallei affords us the ability to put a program in motion that will eventually lead to tests of efficacy for small molecule inhibitors in animal models. Second, a common belief among scientists working on quorum sensing is that it allows a pathogen (or at least a symbiont) to discriminate between a host and a free-living state, Burkholderia mallei is an obligate animal pathogen with no known environmental reservoir. Quorum sensing must be involved in discrimination of different stages or types of infections by this pathogen. Finally, a most obviously, quorum sensing in B. Mallei is a target for anti-S. mallei therapeutic development. Dr. Greenberg proposes to adapt his recently developed quorum sensing reporter system for use in a high-throughput screen for inhibitors. Further experiments will be aimed at identification of quorum-controlled fi. mallei genes. These experiments will involve promoter-trap technology and require the construction of a quorum-sensing regular "gutted strain of B. mallei and or the closely related fi. thailandensis. A new counter-selection method for insertional gene inactiviation in B. thailandensis will be described, as will plans to extend the procedure to B. meillei. This method for generating mutations in members of the B. mallei group represents a major advance that will overcome a current obstacle faced by fi. mallei biologists.
The project will enhance our understanding of virulence in the NIAID Category B Priority Pathogen Burkholderia mallei. The research will shed light on the genetic regulation of virulence factors. Moreover, the research will move towards development of inhibitors of fi. mallei virulence. Obviously, such inhibitors may prove useful as therapeutic agents. The investigations may lead to similar agents for other pathogens.
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