Thiacetazone Research Articles

Metabolic Activation of Thiacetazone by the Flavin Monooxygenase EtaA of Mycobacterium tuberculosis

Thiacetazone (TAZ) and ethionamide (ETA) are thioamide-containing second line antitubercular prodrugs for which there is an impressive clinical history of cross-resistance in M. tuberculosis and M. leprae. The recently identified FAD-containing monooxygenase EtaA has previously been shown to oxidize ETA to a sulfenic acid (-SOH) and eventually to the amide. EtaA is shown here to also be responsible for activation of TAZ. The two metabolites identified in the in vitro oxidation of TAZ by heterologously expressed EtaA are a sulfinic acid (-SO2H) and a carbodiimide (-N=C=NH), both of which apparently derive from an initially formed but not detected sulfenic acid intermediate. The pH dependence of the oxidation of TAZ by EtaA demonstrated that under basic conditions formation of the carbodiimide metabolite is favored, whereas under neutral or acidic conditions the sulfinic acid is preferred. The sulfenic acid intermediate undergoes redox cycling with glutathione whereas the carbodiimide metabolite forms a covalent adduct with glutathione. Analogous reactions are observed with the human flavin monooxygenases FMO1 and FMO2. The metabolites formed provide a possible rationale for the cytotoxicity of TAZ. This work was supported by NIH grant GM56531.

Oxidative Activation of Thiacetazone by the Mycobacterium tuberculosis Flavin Monooxygenase EtaA and Human FMO1 and FMO3

Thiacetazone (TAZ) and ethionamide (ETA) are, respectively, thiourea- and thioamide-containing second line antitubercular prodrugs for which there is an extensive clinical history of cross-resistance in Mycobacterium tuberculosis. EtaA, a recently identified flavin-containing monooxygenase (FMO), is responsible for the oxidative activation of ETA in M. tuberculosis. We report here that EtaA also oxidizes TAZ and identify a sulfinic acid and a carbodiimide as the isolable metabolites. Both of these metabolites are derived from an initial sulfenic acid intermediate. Oxidation of TAZ by EtaA at basic pH favors formation of the carbodiimide, whereas neutral or acidic conditions favor formation of the sulfinic acid. The same metabolites are formed from TAZ by human FMO1 and FMO3. The sulfenic acid and carbodiimide metabolites, but not the sulfinic acid product, readily react with glutathione, the first to regenerate the parent drug and the second to give a glutathione adduct. These reactions may contribute to the antitubercular activity and/or toxicity of TAZ.

Rebuttal: Time to call a halt to emotions in the assessment of thioacetazone

Rebuttal: Time to call a halt to emotions in the assessment of thioacetazone

Use of thioacetazone not cost effective or ethical

Use of thioacetazone not cost effective or ethical

Use of thioacetazone not cost effective or ethical

Use of thioacetazone not cost effective or ethical

Thioacetazone should be abandoned in Africa

Thioacetazone should be abandoned in Africa

Thioacetazone toxicity - developing countries need help

Thioacetazone toxicity - developing countries need help

Thioacetazone toxicity - developing countries need help

Thioacetazone toxicity - developing countries need help

Crystal and Molecular Structure of Thiacetazone.

C 10 H 12 N 4 OS cristallise dans le systeme monoclinique avec le groupe d'espace P2 1 /a. Affinement de la structure jusqu'a 0,041

Genetic effects of drug interaction in tuberculosis patients and their fate.

In this paper we will discuss the genetic consequences of drug interaction in tuberculosis patients. Blood from tuberculosis patients was cultured before, during, and after withdrawal of therapy involving five different drug combinations of isoniazid (INH), thiacetazone (TAZ), para-aminosalicylic acid (PAS), and streptomycin (SM). The approaches used to detect DNA damage were chromosome aberrations and sister chromatid exchanges (SCEs). A total of 179 subjects were analyzed. In combination these drugs showed synergistic, additive, and antagonistic effects, though they were found to be nonclastogenic individually. Four of the drug combinations, INH + TAZ, INH + PAS, INH + TAZ + SM, and INH + PAS + SM, induced a significant increase in the frequency of aberrations, whereas INH + SM did not induce aberrations. In fact, SM appeared to reduce the frequency of aberrations. SCEs were increased in only two patients: one treated with INH + TAZ and the other with INH + PAS. The frequency of aberrations after withdrawal of therapy was decreased; it was slightly higher than the controls, though it was insignificant. The return to normalcy could be due to elimination of damaged cells or the repair of DNA in lymphocytes. Though the drug-induced aberrations do not persist after withdrawal of therapy, the chromosome damaging combinations of drugs should be used with caution, because the possibility of meiotic chromosome damage in germ cells (during therapy), which might be passed on to the next generation, cannot be ruled out.

The early bactericidal activity of drugs in patients with pulmonary tuberculosis.

Counts of colony-forming units of Mycobacterium tuberculosis in sputum were done on selective medium during the first 2 wk of treatment of 124 patients with pulmonary tuberculosis. The 27 chemotherapy regimens studied included daily administration of thiacetazone, p-aminosalicylic acid, pyrazinamide, rifampin, streptomycin, ethambutol, and isoniazid alone and certain 2-drug, 3-drug, and 4-drug combinations. Thiacetazone and p-aminosalicylic acid appeared to be only bacteriostatic. The mean fall in counts and the differences between regimens containing the remaining bactericidal drugs were greater during the first 2 days of treatment than during the remaining 12 days. The early (0-to-2-day) falls were much larger with isoniazid than with other drugs. Rifampin was less bactericidal, and may have reduced the bactericidal activity of the 3-drug and 4-drug combinations, including isoniazid. Although streptomycin and pyrazinamide were only slightly bactericidal alone or in a 2-drug combination, the 3-drug regim...

Natural sensitivity of M. Tuberculosis to thiacetazone

Natural sensitivity of M. Tuberculosis to thiacetazone

Streptomycin, I.N.H. and thiacetazone

Streptomycin, I.N.H. and thiacetazone

Streptomycin, I.N.H., and thiacetazone

Streptomycin, I.N.H., and thiacetazone

Thiacetazone in Tuberculosis

Thiacetazone in Tuberculosis

Amithiozone: mechanism of action and resistance development by mycobacteria.

Amithiozone: mechanism of action and resistance development by mycobacteria.

Antituberculous activity of hinconstarch, a synthetic polymer of isoniazid, amithiozone, and starch.

Antituberculous activity of hinconstarch, a synthetic polymer of isoniazid, amithiozone, and starch.

Observations on the effect of amithiozone (tibione) in selected tuberculous pulmonary lesions.

Observations on the effect of amithiozone (tibione) in selected tuberculous pulmonary lesions.

Experimental studies on the toxicity of amithiozone in dogs.

Experimental studies on the toxicity of amithiozone in dogs.

The hepatic toxicity of amithiozone.

The hepatic toxicity of amithiozone.