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Mechanism of thioamide drug action against tuberculosis and leprosy.

Abstract

Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target-drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.

More information

Type
Journal Article
Author
Wang F
Langley R
Gulten G
Dover LG
Besra GS
Jacobs WR
Sacchettini JC
Year of Publication
2007
Journal
The Journal of experimental medicine
Volume
204
Issue
1
Number of Pages
73-8
Date Published
2007 Jan 22
Language
eng
ISSN Number
0022-1007
DOI
10.1084/jem.20062100
Alternate Journal
J. Exp. Med.
Publication Language
eng

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