Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Control of tuberculosis caused by multidrug-resistant (MDR) Mycobacterium (M.) tuberculosis has become one of the major problems throughout the world. Understanding of the molecular mechanisms of resistance may help in the development of novel methods for the rapid and precise detection of drug-resistant M. tuberculosis. Eight agents have been recommended to treat tuberculosis. Isoniazid (INH), rifampicin (RFP), pyrazinamide (PZA), streptomycin(SM), and ethambutol (EB) are used as the first line agents, and the others are the second line agents. MDR M. tuberculosis strains are resistant both to INH and RFP which have the most effective bactericidal activity to M. tuberculosis. Nearly 95% of RFP resistant strains possess a mutation on the rpoB gene encoding a DNA-dependent RNA polymerase. INH particularly shows an inhibition of the cell wall synthesis of M. tuberculosis and approximately 90% of INH resistant strains have a mutation on the inhA, katG, and ahpG gene encoding enzymes related to a mycolic acid synthesis of cell wall. PZA resistant strains have a mutation on the pncA gene encoding a pyrazinamidase which degradates pyrazinamide to a bactericidal substance, pyrazinoic acid. SM resistant strains have a mutation on the rrs and rpsL gene encoding a 16S rRNA and a S12 ribosomal subunit protein, respectively. EB resistant strains have a mutation on the embB gene encoding a arabinosyl transferase which catalyzes cell wall synthesis. Resistant mechanisms of second-line agents have also been identified. Recently, rapid detection methods for RFP and INH resistant mutations have been developed on the basis of these studies.
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PMID:[Molecular mechanisms of multidrug resistance in Mycobacterium tuberculosis]. 1101 93

Human tuberculosis is still one of the most frequent causes of death worldwide. Despite the implementation of therapeutic regimes combining four drugs, the rise of resistant and multidrug-resistant Mycobacterium tuberculosis strains has compromised their efficacy. Two of the most effective anti-tubercular drugs in use, rifampicin and isoniazid, have been closely studied due to their therapeutic importance. These studies have led to the identification of the genes involved in resistance mechanisms and of those encoding the molecular targets for these drugs. Rifampicin is an inhibitor of the beta-subunit of the RNA polymerase of prokaryotes, including M. tuberculosis. Resistance to rifampicin is mediated by mutations clustered in a small region of the rpoB gene. A fraction of resistant strains showed no mutations in rpoB, suggesting that other mechanisms of resistance, possibly efflux pumps, may exist. Isoniazid is a pro-drug activated by KatG, a catalase-peroxidase. Mutations in katG, the most commonly found in M. tuberculosis clinical isolates, give high levels of resistance. In spite of this, the molecular target for isoniazid is InhA, an enoyl-ACP-reductase involved in the biosynthesis of mycolic acids. Other mutations causing resistance to isoniazid have been mapped to ndh, a gene encoding the NADH dehydrogenase.
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PMID:[Mechanisms of action of and resistance to rifampicin and isoniazid in Mycobacterium tuberculosis: new information on old friends]. 1703 59

Isoniazid (INH) is a cornerstone of antitubercular therapy. Mycobacterium tuberculosis complex bacteria are the only mycobacteria sensitive to clinically relevant concentrations of INH. All other mycobacteria, including M. marinum and M. avium subsp. paratuberculosis are resistant. INH requires activation by bacterial KatG to inhibit mycobacterial growth. We tested the role of the differences between M. tuberculosis KatG and that of other mycobacteria in INH sensitivity. We cloned the M. bovis katG gene into M. marinum and M. avium subsp. paratuberculosis and measured the MIC of INH. We recombinantly expressed KatG of these mycobacteria and tested in vitro binding to, and activation of, INH. Introduction of katG from M. bovis into M. marinum and M. avium subsp. paratuberculosis rendered them 20 to 30 times more sensitive to INH. Analysis of different katG sequences across the genus found KatG evolution diverged from RNA polymerase-defined mycobacterial evolution. Biophysical and biochemical tests of M. bovis and nontuberculous mycobacteria (NTM) KatG proteins showed lower affinity to INH and substantially lower enzymatic capacity for the conversion of INH into the active form in NTM. The KatG proteins of M. marinum and M. avium subsp. paratuberculosis are substantially less effective in INH activation than that of M. tuberculosis, explaining the relative INH insensitivity of these microbes. These data indicate that the M. tuberculosis complex KatG is divergent from the KatG of NTM, with a reciprocal relationship between resistance to host defenses and INH resistance. Studies of bacteria where KatG is functionally active but does not activate INH may aid in understanding M. tuberculosis INH-resistance mechanisms, and suggest paths to overcome them.
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PMID:Differential Sensitivity of Mycobacteria to Isoniazid Is Related to Differences in KatG-Mediated Enzymatic Activation of the Drug. 3231 66