@article{7259,
  keywords = {Antitubercular Agents, Bacterial Proteins, Crystallography, X-Ray, Drug Design, Drug Resistance, Multiple, Bacterial, Ethionamide, Humans, In Vitro Techniques, Leprostatic Agents, leprosy, Models, Molecular, Mycobacterium avium Complex, Mycobacterium avium-intracellulare Infection, Mycobacterium leprae, Mycobacterium tuberculosis, NAD, Oxidoreductases, Prothionamide, Tuberculosis, Tuberculosis, Multidrug-Resistant},
  author = {Wang F and Langley R and Gulten G and Dover LG and Besra G and Jacobs W and Sacchettini JC},
  title = {Mechanism of thioamide drug action against tuberculosis and leprosy.},
  abstract = {<p>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.</p>},
  year = {2007},
  journal = {The Journal of experimental medicine},
  volume = {204},
  pages = {73-8},
  month = {2007 Jan 22},
  issn = {0022-1007},
  doi = {10.1084/jem.20062100},
  language = {eng},
}