Mechanism of thioamide drug action against tuberculosis and leprosy

Feng Wang, Robert Langley, Gulcin Gulten, Lynn G. Dover, Gurdyal S. Besra, William R. Jacobs, James C. Sacchettini

Research output: Contribution to journalArticle

176 Scopus citations

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. JEM

Original languageEnglish (US)
Pages (from-to)73-78
Number of pages6
JournalJournal of Experimental Medicine
Volume204
Issue number1
DOIs
StatePublished - Jan 22 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Wang, F., Langley, R., Gulten, G., Dover, L. G., Besra, G. S., Jacobs, W. R., & Sacchettini, J. C. (2007). Mechanism of thioamide drug action against tuberculosis and leprosy. Journal of Experimental Medicine, 204(1), 73-78. https://doi.org/10.1084/jem.20062100