: This proposal has the objective of designing inhibitors against latent, persistent, and drug-resistant tuberculosis. This objective will be pursued using the following methods: (1) The applicant will perform bioinformatic analysis of implicated Tb genes. This data will be combined with the results of genetic analyses performed by our collaborators to identify the most promising protein candidates for inhibitor design. (2) The structures of the protein candidates identified in part (1) will be determined using x-ray crystallography. (3) The crystal structures will be used for structure- based inhibitor design. Computational methods will be used to screen large databases of potential inhibitors. Knowledge of protein chemistry and visual analysis will be used to design derivatives of promising inhibitors that inhibit the target protein more specifically and effectively, and that reduce the risks of non-specific binding to other proteins and enzymes.
