Hexameric PBGS as a Bioterrorism Defense

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DESCRIPTION (provided by applicant): National defense requires development of novel strategies to combat potential bio-terrorism agents. One target of this strategy is the development of new antimicrobial agents. The Jaffe laboratory has identified a hexamer-octamer equilibrium as the structural basis for allosteric control of a key enzyme in tetrapyrrole biosynthesis, porphobilinogen synthase (PBGS). Trapping of the inactive hexamer is proposed as a basis for discovery of new antimicrobials directed against the NIAID priority pathogens Burkholderia pseudomallei, Brucella mefitensis, Burkholderia mallei, Rickettsia prowazekii, Vibrio cholerae, and Yersinia enterocolitica. The aims of this exploratory proposal are: 1) To build protein structure models for hexamers of PBGS from these pathogens; 2) To use computational docking procedures to discover molecules that will preferentially bind to and stabilize the hexamer; and 3) To test the identified molecules for their ability to inhibit the PBGS of these pathogens while not inhibiting human PBGS. The current proposal describes a high risk - high impact exploratory project. Success of the proposed studies will establish a much needed new target for species selective antibiotic development that can be applied to bio-defense against NIAID priority pathogens.