Mechanism of thioamide drug action against tuberculosis and leprosy.
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.
Wang
Feng
F
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
Langley
Robert
R
Gulten
Gulcin
G
Dover
Lynn G
LG
Besra
Gurdyal S
GS
Jacobs
William R
WR
Sacchettini
James C
JC
D000995:Antitubercular Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D018360:Crystallography, X-Ray; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D005000:Ethionamide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007917:Leprostatic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007918:Leprosy / Q000188:drug therapy*; D008958:Models, Molecular; D015269:Mycobacterium avium Complex / Q000187:drug effects / Q000201:enzymology; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy; D009166:Mycobacterium leprae / Q000187:drug effects / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011515:Prothionamide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D007917:Leprostatic Agents; D009243:NAD; D011515:Prothionamide; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D005000:Ethionamide