The Journal of Experimental Medicine
StemCell Technologies
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Published online January 16, 2007
doi:10.1084/jem.20062100
The Journal of Experimental Medicine, Vol. 204, No. 1, 73-78
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Wang et al.
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BRIEF DEFINITIVE REPORT

 Mechanism of thioamide drug action against tuberculosis and leprosy

Feng Wang1, Robert Langley1, Gulcin Gulten1, Lynn G. Dover3, Gurdyal S. Besra3, William R. Jacobs, Jr.2, and James C. Sacchettini1

1 Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843
2 Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461
3 School of Biosciences, University of Birmingham, Birmingham B15 2TT, England, UK

CORRESPONDENCE James C. Sacchettini: sacchett{at}tamu.edu

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.


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