Regulation of Fatty Acid Biosynthesis and Degradation in Pseudomonas aeruginosa

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DESCRIPTION (provided by applicant): Replication of Pseudomonas aeruginosa to very high-cell-density (HCD) in the lung allows the bacteria to quorum-sense and secrete numerous virulence toxins, causing severe and chronic lung infections in cystic fibrosis (CF) patients. Central to these processes are Fatty acid biosythesis (Fab) and fatty acid degradation (Fad). Fab is responsible for the syntheses of two virulence-controlling acylated-homoserine- lactone (AHL) molecules in P. aeruginosa, and Fad contributes to phosphatidylcholine (PC) metabolism in the Cystic Fibrosis lung as a nutrient source. Hence, both Fab- and Fad-pathways are critical for the pathogenesis of P. aeruginosa by allowing HCD replication and producing two AHL quorum-sensing molecules. Regulation of both pathways is largely unknown. The working hypothesis, based on our preliminary data, is that Fab and Fad are coordinately inverse regulated in P. aeruginosa, by up-regulating one pathway and down-regulating the other. Based on this working hypothesis, we propose to: i) identify and characterize the regulator that controls fabAB and one of the fadBA-operons important for PC metabolism and ii) perform microarray experiments to establish other Fad or Fab related genes that are regulated in the same regulon. Identifying this regulatory protein that controls both pathways, at the genetic level, is the key to understanding physiology and control of processes that are critical for the pathogenesis of P. aeruginosa. In addition, it will contribute to the identification of other fad-genes in the same regulon that could contribute to nutrient utilization in the CF lung. P. aeruginosa is an emerging and re-emerging infectious agent that causes serious burdens to public health, because it is a major culprit of hospital-acquired pneumonia and causes prolonged suffering and high mortality to hundreds of thousands of people (mostly children) with CF. Hence, it is expected that these studies will contribute to innovative approaches for improved treatment to extend the lives of CF patients with debilitating chronic lung infections.