Quorum Sensing in Burkholderia mallei: An Antivirulence Therapeutic Target

PI: Dr. E. Peter Greenberg

Department of Microbiology
University of Washington, Seattle, WA

Bacterial quorum sensing involves small molecule cell-cell signaling 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 Pseudomonas 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-B. mallei therapeutic development.

Dr. Greenberg has adapted his recently developed quorum sensing reporter system for use in a high-throughput screen for inhibitors. Experiments are aimed at identification of quorum-controlled B. mallei genes. These experiments involve promoter-trap technology and require the construction of a quorum-sensing regulator “gutted strain of B. mallei and or the closely related B. thailandensis. A new counter-selection method for insertional gene inactivation in B. thailandensis was developed and the procedure has been extended to B. mallei. This method for generating mutations in members of the B. mallei group represents a major advance that has overcome a current obstacle faced by B. mallei biologists.