The emergence and increasing prevalence of bacterial strains resistant to antibiotics demand the discovery of new therapeutic approaches. Inhibition of pathogenesis by targeting bacterial virulence represents a promising alternative for antimicrobial therapy. A central requirement of bacterial virulence is the ability to tightly regulate virulence genes in response to host signals. Besides the two-component regulatory system, cell-surface signaling (CSS) represents an important mechanism by which bacteria respond to the medium. However, whereas regulation by two-component systems has been studied in great detail, little emphasis has been on CSS regulation, although it offers great potential for the development of antimicrobial compounds. In this project I propose to characterize a novel CSS regulatory system (PUMA3) which I recently discovered and that triggers the production of Pseudomonas aeruginosa virulence factors in response to a (human) host signal. P. aeruginosa is a major human opportunistic pathogen causing infections in hospitalized patients. It is also the main cause of death of patients suffering from cystic fibrosis. Due to its natural resistance to antibiotics and its ability to acquire such resistance, P. aeruginosa infections are often difficult to treat. The P. aeruginosa PUMA3 system consists of an extracytoplasmic function (ECF) sigma factor, a sigma factor regulator in the cytoplasmic membrane, and a receptor. Presence of an inducing signal results in the activation of the sigma factor, which binds to the RNA polymerase and promotes the transcription of a specific set of virulence genes. Induction of PUMA3 increases P. aeruginosa virulence. In this project I will characterize this novel regulatory system in detail, identify the inducing conditions and study variants in other Gram-negative pathogens. Moreover, a high-throughput screen will be developed to target ECF sigma factors in order to find new drugs that prevent P. aeruginosa virulence.
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