02369nas a2200445   4500000000100000008004100001260001600042653002600058653002300084653002700107653001600134653004100150653001600191653001100207653002400218653002300242653001200265653002200277653003200299653004900331653002500380653003100405653000800436653002000444653001800464653001700482653003800499100001100537700001400548700001300562700001300575700001200588700001300600700001900613245007300632300000900705490000800714520118700722022001401909       2007                            d  c2007 Jan 2210aAntitubercular Agents10aBacterial Proteins10aCrystallography, X-Ray10aDrug Design10aDrug Resistance, Multiple, Bacterial10aEthionamide10aHumans10aIn Vitro Techniques10aLeprostatic Agents10aleprosy10aModels, Molecular10aMycobacterium avium Complex10aMycobacterium avium-intracellulare Infection10aMycobacterium leprae10aMycobacterium tuberculosis10aNAD10aOxidoreductases10aProthionamide10aTuberculosis10aTuberculosis, Multidrug-Resistant1 aWang F1 aLangley R1 aGulten G1 aDover LG1 aBesra G1 aJacobs W1 aSacchettini JC00aMechanism of thioamide drug action against tuberculosis and leprosy.  a73-80 v2043 a<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>  a0022-1007