thioacetazone and thiocarlide

One of the first approaches undertaken in the quest for antitubercular compounds was that of understanding the mechanism of action of old drugs and proposing chemical modifications or other strategies to improve their activity, generally lost to the mechanisms of resistance developed by Mycobacterium tuberculosis. A leading case was the work carried out on a set of compounds with proven activity on the essential pathway of the synthesis of mycolic acids. As a result, different solutions were presented, improving the activity of those inhibitors or producing novel compounds acting on the same molecular target(s), but avoiding the most common resistance strategies developed by the tubercle bacilli. This review focuses on the activity of those compounds, developed following the completion of the studies on several of the classic antitubercular drugs.

Topics: Antitubercular Agents; Drug Design; Drug Resistance, Multiple, Bacterial; Ethionamide; Humans; Isoniazid; Mycobacterium tuberculosis; Mycolic Acids; Phenylthiourea; Structure-Activity Relationship; Thioacetazone; Tuberculosis, Pulmonary

A chemical activation study of the thiocarbonyl-type antitubercular prodrugs, ethionamide (ETH), thioacetazone (TAZ), and isoxyl (ISO), was performed. Biomimetic oxidation of ethionamide using H

Topics: Antitubercular Agents; Ethionamide; Hydrogen Peroxide; Models, Molecular; Oxidation-Reduction; Phenylthiourea; Prodrugs; Thioacetazone

Ethionamide (ETH) is a second-line drug for the treatment of tuberculosis. As a prodrug, ETH has to be activated by EthA. ethA is controlled by its repressor EthR. 2-Phenylethyl-butyrate (2-PEB) inhibits EthR binding, enhances expression of EthA, and thereby enhances the growth-inhibitory effects of ethionamide, isoxyl, and thiacetazone in Mycobacterium tuberculosis strains with resistance to ETH due to inhA promoter mutations but not ethA mutations.

Topics: Antitubercular Agents; Bacterial Proteins; Butyrates; Drug Resistance, Multiple, Bacterial; Drug Synergism; Ethionamide; Gene Expression Regulation, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Oxygenases; Phenylthiourea; Thioacetazone

Isoxyl (ISO) and thiacetazone (TAC), two prodrugs once used in the clinical treatment of tuberculosis, have long been thought to abolish Mycobacterium tuberculosis (M. tuberculosis) growth through the inhibition of mycolic acid biosynthesis, but their respective targets in this pathway have remained elusive. Here we show that treating M. tuberculosis with ISO or TAC results in both cases in the accumulation of 3-hydroxy C(18), C(20), and C(22) fatty acids, suggestive of an inhibition of the dehydratase step of the fatty-acid synthase type II elongation cycle. Consistently, overexpression of the essential hadABC genes encoding the (3R)-hydroxyacyl-acyl carrier protein dehydratases resulted in more than a 16- and 80-fold increase in the resistance of M. tuberculosis to ISO and TAC, respectively. A missense mutation in the hadA gene of spontaneous ISO- and TAC-resistant mutants was sufficient to confer upon M. tuberculosis high level resistance to both drugs. Other mutations found in hypersusceptible or resistant M. tuberculosis and Mycobacterium kansasii isolates mapped to hadC. Mutations affecting the non-essential mycolic acid methyltransferases MmaA4 and MmaA2 were also found in M. tuberculosis spontaneous ISO- and TAC-resistant mutants. That MmaA4, at least, participates in the activation of the two prodrugs as proposed earlier is not supported by our biochemical evidence. Instead and in light of the known interactions of both MmaA4 and MmaA2 with HadAB and HadBC, we propose that mutations affecting these enzymes may impact the binding of ISO and TAC to the dehydratases.

Topics: Alleles; Antitubercular Agents; Cell Wall; Chromatography, Liquid; Fatty Acid Synthases; Gas Chromatography-Mass Spectrometry; Genome, Bacterial; Lipids; Mass Spectrometry; Models, Chemical; Mycobacterium bovis; Mycobacterium tuberculosis; Mycolic Acids; Phenylthiourea; Recombinant Proteins; Sequence Analysis, DNA; Thioacetazone; Time Factors

Topics: Animals; Drug Therapy, Combination; Leprosy; Mice; Phenylthiourea; Sulfamethoxypyridazine; Thioacetazone

Topics: Drug Resistance, Microbial; Ethionamide; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenylthiourea; Thioacetazone; Tuberculosis

Topics: Culture Media; Drug Combinations; Drug Resistance; Drug Resistance, Microbial; Evaluation Studies as Topic; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenylthiourea; Thioacetazone; Thiosemicarbazones; Tuberculosis

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Drug Combinations; Evaluation Studies as Topic; Humans; Isoniazid; Phenylthiourea; Streptomycin; Thioacetazone; Tuberculosis, Renal

Topics: Agar; Aminosalicylic Acids; Animals; Culture Media; Depression, Chemical; Drug Resistance, Microbial; Egg Yolk; Ethionamide; Female; Glycerol; Isoniazid; Mycobacterium tuberculosis; Phenylthiourea; Streptomycin; Surface-Active Agents; Thioacetazone