Development of Chemical Inhibitors of Pseudomonas Aeruginosa Alginate Production

Grants and Contracts Details


ABSTRACT Pseudomonas aeruginosa is a bacterial pathogen that is associated with a decline in lung function in cystic fibrosis (CF) patients. In particular, the life-long colonization of CF patients with the same initial strain of P. aeruginosa indicates both failure with current therapeutics and difficulty in the development of treatment options. Over the course of this chronic infection, P. aeruginosa undergoes a slow rate of mutation that eventually leads to mutation of the mutS gene that is responsible for DNA repair of replication errors. As a consequence, the mucA gene is mutated, leading to constitutive activation of the AlgU sigma factor that leads to constitutive transcription of the algD-A operon that encodes the alginate biosynthetic machinery. Since the mucA mutation inactivates the function of the MucA protein, it is difficult to restore the function of MucA to sequester AlgU, since any bacterium that is made wild-type will be eliminated from the population. Thus, an alternative approach is required to prevent the function of the alginate biosynthetic complex. The complex requires an allosteric activator called cyclic-di-GMP (c-di- GMP) to bind the Alg44 receptor in order to produce the alginate polysaccharide. The Lee lab has recently found two classes of inhibitors that (i) block c-di-GMP synthesis and (ii) prevent c-di-GMP from binding Alg44. Of these two classes of inhibitors, ebselen (Eb) has been previously demonstrated to be safe for human use through testing in several Phase III clinical trials. We have recently published work showing that EbO can effectively block alginate production by P. aeruginosa. In this proposal, we have formed a collaborative team between Dr. Sylvie Garneau-Tsodikova at University of Kentucky who is an expert in the synthesis of Eb analogues and Dr. Vincent Lee at University of Maryland who has expertise in P. aeruginosa alginate production. Together, we seek to: (1) optimize Eb and EbO for alginate inhibition by structure-activity relationship studies and (2) identify the target of inhibition for Eb, EbO, and related analogues. These two synergistic aims will aid the development of potent alginate inhibitors through an iterative process that can be used for future clinical studies. SCOPE OF WORK Dr. Sylvie Garneau-Tsodikova at University of Kentucky will be responsible for all chemical synthesis of Aims 1a and 1b as well as mammalian cytotoxicity assays of Aim 1c. She will also be responsible for target(s) identification in P. aeruginosa of Aim 2c.
Effective start/end date5/1/224/30/23


  • University of Maryland at College Park: $70,000.00


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