Structure-based drug mechanism study and inhibitor design targeting tuberculosis

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Title: Structure-based drug mechanism study and inhibitor design targeting tuberculosis
Author: Wang, Feng
Abstract: 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 ? -lactamase (BlaC ) and fatty -acyl -CoA thioesterase (FcoT ) . Mtb ? -lactamase has been proposed to be the most significant reason for mycobacterial resistance to ? -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 ? -lactamase inhibitors that could be used with ? -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 .
URI: http : / /hdl .handle .net /1969 .1 /ETD -TAMU -1439
Date: 2009-05-15

Citation

Structure-based drug mechanism study and inhibitor design targeting tuberculosis. Available electronically from http : / /hdl .handle .net /1969 .1 /ETD -TAMU -1439 .

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