Isoniazid is a first-line antibiotic used in the treatment of infections caused by Mycobacterium tuberculosis.Isoniazid is a prodrug requiring oxidative activation by the catalase-peroxidase hemoprotein, KatG. Resistance to isoniazid can be obtained by point mutations in the katG gene, with one of the most common being a threonine-for-serine substitution at position 315 (S315T). The S315T mutation is found in more than 50% of isoniazid-resistant clinical isolates and results in an Ϸ200-fold increase in the MIC of isoniazid compared to that for M. tuberculosis H37Rv. In the present study we investigated the hypothesis that superoxide plays a role in KatG-mediated isoniazid activation. Plumbagin and clofazimine, compounds capable of generating superoxide anion, resulted in a lower MIC of isoniazid for M. tuberculosis H37Rv and a strain carrying the S315T mutation. These agents did not cause as great of an increase in isoniazid susceptibility in the mutant strain when the susceptibilities were assessed by using the inhibitory concentration that causes a 50% decrease in growth. These results provide evidence that superoxide can play a role in isoniazid activation. Since clofazimine alone has antitubercular activity, the observation of synergism between clofazimine and isoniazid raises the interesting possibility of using both drugs in combination to treat M. tuberculosis infections.Entering the 21st century, Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a major cause of morbidity and mortality worldwide. TB causes 1.9 million deaths annually among a pool of infected individuals close to 2 billion people (47).Isoniazid (INH) is one of the most effective and widely used therapeutic agents for the treatment of TB. M. tuberculosis shows exceptional sensitivity to INH, being several orders of magnitude more sensitive than most other bacterial species. Much is known about the mechanism of INH activation, including that fact that it is a prodrug requiring activation by the catalase-peroxidase hemoprotein, KatG (13,18,19), in a process that requires molecular oxygen (49). It has been further shown that the activated form of INH forms a covalent adduct with NAD ϩ to generate a potent inhibitor of the InhA protein of M. smegmatis, an enoyl-acyl carrier protein reductase important in mycolic acid biosynthesis (26,30,40). Recent investigations have led to the hypothesis that the sensitivity of M. tuberculosis to INH may be governed by the level of expression of the alkyl hydroperoxide reductase, AhpC, since M. tuberculosis does not express the ahpC gene due to inactivation of the oxidative stress regulatory gene oxyR (5, 6, 32, 38, 52).Nevertheless, specific details regarding the mechanism of action of INH, such as the chemical nature of the activated form of INH, have yet to be determined. For example, InhA as the primary target for INH in M. tuberculosis has been questioned following the discovery of a covalent complex of INH, acyl carrier protein (AcpM), and the -ketoacyl acyl carrier protein...
1. Introduction 2. Results 3. Asteraceae 3.1. Genus Artemisia L. 3.1.1. Artemisia annua L. 3.1.2. Artemisia vulgaris L. 3.1.3. Artemisia absinthium L. (warmwood) 3.1.4. Artemisia scoparia W. et K. 3.1.5. Artemisia camprestris L. 3.2. Genus Ambrosia L. 3.2.1. Ambrosia artemisiifolia L. (the common rag weed) 3.3. Genus Tanacetum L. ( syn. Chrysanthemum L.) 3.3.1. Tanacetum parthenium L. (feverfew) 3.3.2. Tanacetum serotinum L. 3.3.3. Tanacetum vulgare L. (tansy) 3.3.4. Tanacetum macrophyllum Willd. 3.3.5. Tanacetum corymbosum L. 3.4. Genus Telekia Baumg. 3.4.1. Telekia speciosa (Schreb.) Baumg. 3.5. Genus Inula L. 3.5.1. Inula helenium L. 3.5.2. Inula spiraeifolia L. 3.6. Genus Eupatorium L. 3.6.1. Eupatorium cannabinum L. 3.7. Genus Achillea L. 3.7.1. Achillea abrotanoides Vis. 3.7.2. Achillea millefolium subsp. pannonica 3.7.3. Achillea crithmifolia W. et K. 3.7.4. Achillea clypeolata Sibth. et Sm. 3.7.5. Achillea serbica Nyman 3.7.6. Achillea depressa Janka 3.8. Genus Anthemis L. 3.8.1. Anthemis carpatica Willd. 3.8.2. Anthemis cretica L. subsp. cretica 3.9. Genus Centaurea L. 3.9.1. Centaurea derventana Vis. et Pan~. 3.9.2. Centaurea kosaninii Hayek 3.9.3. Centaurea solstitialis L. 4. Apiaceae 4.1. Genus Laserpitium L. 4.1.1. Laserpitium siler L. 4.1.2. Laserpitium marginatum L. 4.1.3. Laserpitium latifolium L. 4.1.4. Laserpitium alpinum W. K. 4.2. Genus Angelica L. 4.2.1. Angelica silvestris L. 4.3. Genus Peucedanum L. 4.3.1. Peucedanum austriacum (Jacq.) Koch
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.