The increase of multi-drug resistant and extensively drug resistant tuberculosis (TB) cases makes it urgent to develop a new generation of TB drugs to counter resistance and shorten treatment. Structural biology, which allows us to “visualize” macromolecules, is now playing a key role in drug discovery. In this work, a structure-based approach was applied to the study of the mode of action of current TB chemotherapies, the identification of potential therapeutic targets, and the design of new inhibitors against TB. Knowledge of the precise mechanisms of action of current TB chemotherapies will provide insights into designing new drugs that can overcome drug-resistant TB cases. Structural biology combined with biochemical and genetic approaches was used to elucidate the mechanisms of actions of isoniazid, ethionamide and prothionamide. The active forms of these anti-TB prodrugs were identified by protein crystallography and the target-inhibitor interactions were revealed by the complex structures. Although these drugs are activated through two completely different routes, they all inhibit InhA, an essential enzyme in mycolic acid biosynthesis, by modification of the enzyme cofactor NAD, which unveils a novel paradigm of drug action. Isoniazid, ethionamide and prothionamide all target InhA, which validates the enzyme as a superb drug target. A structure-based approach was adopted to design new inhibitors targeting InhA, using triclosan as the scaffold. Guided by the InhA-inhibitor complex structures, two groups of triclosan analogs were identified with dramatically increased inhibitory activity against InhA. Structural biology has also provided fundamental knowledge of two potential therapeutic targets, Mtb β-lactamase (BlaC) and fatty-acyl-CoA thioesterase (FcoT). Mtb β-lactamase has been proposed to be the most significant reason for mycobacterial resistance to β-lactam antibiotics. The determination of Mtb BlaC structure not only demonstrates the mechanism of drug resistance but also provides a solid base for the design of new β-lactamase inhibitors that could be used with β-lactam antibiotics as a new regimen to treat tuberculosis. The crystal structure of FcoT provided crucial information in identification of the function of this previously hypothetical protein. The characterization of FcoT revealed an important pathway that is critical for Mtb’s survival in host macrophages.
| Identifer | oai:union.ndltd.org:TEXASAandM/oai:repository.tamu.edu:1969.1/ETD-TAMU-1439 |
| Date | 15 May 2009 |
| Creators | Wang, Feng |
| Contributors | Sacchettini, James C., Burgess, Kevin, Gabba?Fran?s P., Leibowitz, Julian |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | thesis, text |
| Format | electronic, application/pdf, born digital |
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