Mechanism of thioamide drug action against tuberculosis and leprosy

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.

Antibacterial targets in fatty acid biosynthesis

“…Their mechanism of action has been assumed to be the same as isoniazid, which is a pro-drug that requires enzymatic activation by a catalase-peroxidase (KatG) to react with NAD + and form the adduct which is the proximal inhibitor of FabI. It has now been shown that ethionamide and prothionamide act through formation of similar adducts, but are activated by a flavin monooxygenase EthA, rather than KatG [24].…”

Metabolism of the Antituberculosis Drug Ethionamide

“…However, the sulfinic acid has not been isolated yet. The activation of ETH by the M. tuberculosis EtaA was also extended to other related compounds [36], such as thiacetoazone, PTA and isoxy (4,4 -diisoamyloxydiphenyl-thiourea) [37][38][39]. Magic angle spinning NMR studies in living mycobacterial cells on the EtaA-dependent oxidation of ETH have shown that the formation of the S-oxide and 4-pyridylmethanol metabolites are formed primarily outside the cells, and the accumulation of a unidentified activated intermediate formed inside the cells [40,41].…”

“…Gene array studies have shown that both ETH and INH induce similar patterns of protein expression [74], and mutations in the InhA gene give rise to resistance to both ETH and INH [45,75]. In addition, it has also been shown that both activated ETH and PTA inhibit EtaA [37], and that the basis for the inhibition of InhA by ETH and PTA yields ETA-NADH and PTA-NADH adducts, respectively, which are similar to the adduct obtained with INH [37]. The formation mechanism of the activated ETH molecule is possible due to the formation of the S-oxide preceded by hydrolysis of the putative sulfinic acid to give the amide [35].…”

A synthetic mammalian gene circuit reveals antituberculosis compounds

“…bacterial nicotinamide adenine dinucleotide derivative (3,17). EthR-mediated repression of ethA transcription requires rather high clinical doses of ethionamide [up to 1g/day (6, 18)], which is associated with severe side effects including neurotoxicity (19) and fatal hepatotoxicity (6), yet is often still insufficient to reach minimum inhibitory levels in the bloodstream (20).…”

“…During 35 years of its clinical use, ethionamide has fortunately elicited little cross-resistance with isoniazid because both prodrugs have to be activated by different mycobacterial enzymes to develop their antimicrobial activity (2). Ethionamide is activated by the Baeyer-Villiger monooxygenase EthA, which converts the prodrug into an antimycobacterial nicotinamide adenine dinucleotide derivative (3,4). Because ethA is repressed by EthR (5), ethionamide-based tuberculosis therapy is often unsuccessful even when prescribed at high hepatotoxic doses (6).…”