Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant strains have created a need for the development of new antimycobacterial agents. Mycolic acids, the hallmark of mycobacteria, are high-molecular-weight alpha-alkyl, beta-hydroxy fatty acids, which appear mostly as bound esters in the mycobacterial cell wall. The product of the M. tuberculosis inhA structural gene (InhA) has been shown to be the primary target for isoniazid (INH), the most prescribed drug for active TB and prophylaxis. InhA was identified as an NADH-dependent enoyl-ACP reductase specific for long-chain enoyl thioesters. InhA is a member of the mycobacterial Type II fatty acid biosynthesis system, which elongates acyl fatty acid precursors of mycolic acids. Although the history of chemotherapeutic agent development demonstrates the remarkably successful tinkering of a few structural scaffolds, it also emphasizes the ongoing, cyclical need for innovation. The main focus of our contribution is on new data describing the rationale for the design of a pentacyano(isoniazid)ferrateII compound that requires no KatG-activation, its chemical characterization, in vitro activity studies against WT and INH-resistant I21V M. tuberculosis enoyl reductases, the slow-onset inhibition mechanism of WT InhA by the inorganic complex, and molecular modeling of its interaction with WT InhA. This inorganic complex represents a new class of lead compounds to the development of anti-tubercular agents aiming at inhibition of a validated target.
 ...
PMID:Slow-onset inhibition of 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis by an inorganic complex. 1684 88

The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.
 ...
PMID:Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis. 1687 Jul 53

Testing the direct nitrate reductase technique versus the absolute concentration test has indicated that the former may be successfully used for rapid determination of the sensitivity of Mycobacterium tuberculosis (MBT) to isoniazid and rifampicin and it can reduce the time of obtaining a result by 4-5 times in the cases that sputum bacterioscopy yielded a positive result that allows the modified method to be applied. The advantages of the TB-Biochip technique are the time of detection multidrug-resistant MBT (24 hours), a possibility of obtaining these data just when analyzing sputum-isolated MBT DNA, and characterization of the MBT genomic elements that are responsible for drug sensitivity to antituberculous agents, by determining mutations in the examined genes and this all by using one chip. The agreement of results of microbiological and molecular genetic studies study of drug MBT sensitivity was 98%. There were no differences in the results of those using isoniazid. As for rifampicin, there was a difference in two samples (3.8%). Analysis of a combination of mutations forming multidrug resistance indicated that 74.3% of multidrug-resistant MBT isolates had mutations in the codon Ser531 > Lue of the rpoB gene and in the codon Ser315 > Thr of the katG gene. 97.4% of strains with signs of multidrug resistance had mutations in the codon 315 of the katG gene. 20.5% of isoniazid-resistant strains were observed to have mutations in two genes (katG and inhA) and 28.2% of the strains exhibited double mutation in the katG gene - Ser315Thr and Ile335 > Val.
 ...
PMID:[Determination of multidrug resistance of M. tuberculosis by different methods]. 1688 Dec 35

Isoniazid is one of the most effective antituberculosis drugs, yet its precise mechanism of action is still controversial. Using specialized linkage transduction, a single point mutation allele (S94A) within the putative target gene inhA was transferred in Mycobacterium tuberculosis. The inhA(S94A) allele was sufficient to confer clinically relevant levels of resistance to isoniazid killing and inhibition of mycolic acid biosynthesis. This resistance correlated with the decreased binding of the INH-NAD inhibitor to InhA, as shown by enzymatic and X-ray crystallographic analyses, and establishes InhA as the primary target of isoniazid action in M. tuberculosis.
 ...
PMID:Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid. 1690 55

To evaluate the efficiency of chemotherapy used in patients with pulmonary tuberculosis by the results of a rapid detection of drug resistance (DR) to isoniazid and rifampicin on a "TB-Biochip" test system versus the standard treatment with its subsequent correction by the data of determination of Mycobacterium tuberculosis (MBT) resistance by the absolute concentration technique (ACT), the study included 208 patients with pulmonary tuberculosis. The patients were divided into 2 groups: 1) those in whom MBT sensitivity to antituberculous agents was determined on a "TB-Biochip" test system to detect mutations in the MBT genes rpoB, katG, inhA, ahpC that were responsible for MBT sensitivity to rifampicin and isoniazid and by ACT; 2) those in whom this was determined by only ACT. The results of a test for MBT sensitivity to rifampicin and isoniazid were obtained within 2 days before chemotherapy in Group 1 and 2 months after chemotherapy in Group 2. In Group 1, antituberculous chemotherapy was used, by taking into account MBT sensitivity to isoniazid, rifampicin, or their combination; in Group 2, the drugs were given by the standard regimens with their subsequent correction following 2 months by the results of ACT. The timely initiation of treatment with reserve drugs in the detection of drug sensitivity in MBT could achieve higher therapeutic efficiency and in a shorter space of time.
 ...
PMID:[Efficiency of chemotherapy of destructive pulmonary tuberculosis, based on the results of rapid detection of drug sensitivity to isoniazid and rifampicin with the "TB-Biochip" test system]. 1700 52

We assessed the performance of the Genotype MTBDR line probe assay that offers the simultaneous identification of Mycobacterium tuberculosis and its resistance to rifampin (RIF) and isoniazid (INH) by detecting the most commonly found mutations in the rpoB and katG genes. One hundred thirteen M. tuberculosis isolates were tested. The nucleotide sequences of the katG and inhA genes and the mabA-inhA promoter region were also determined. The MTBDR assay detected 100% and 67% (n = 64) of the strains resistant to RIF and INH, respectively. Among the latter, 62 strains carried a Ser315Thr mutation in katG, 59 of them displaying a high level of resistance to INH. Two strains with a low level of INH resistance had a Ser315Asn mutation. No mutation was found by the MTBDR assay for 31 INH-resistant strains (33%), of which 24 showed a low level of resistance. By DNA sequencing, we found among them various mutations in the KatG protein for 7 strains, a C-->T mutation in position -15 of the mabA-inhA promoter in 17 strains, and a Ser94Ala mutation in InhA for 7 strains. In conclusion, the MTBDR assay, which fits easily in the workflow of a routine laboratory, enabled the detection of 100% of the RIF-resistant strains and 89% of the INH-resistant strains with a high level of resistance but only 17% of the strains characterized by a low level of INH resistance, indicating that the test can be used as a rapid method to detect in the same experiment the rifampin-resistant and the high-level isoniazid-resistant strains of M. tuberculosis.
 ...
PMID:Performance of the genotype MTBDR line probe assay for detection of resistance to rifampin and isoniazid in strains of Mycobacterium tuberculosis with low- and high-level resistance. 1702 Oct 94

Drug-resistant tuberculosis poses a significant problem for treatment. The mechanisms of resistance to the front-line drug isoniazid (INH) are complex and can be mediated by katG, inhA and other unknown genes. To identify the percentage of INH-resistant strains with no katG or inhA mutation, this study characterized a panel of 28 clinical isolates of Mycobacterium tuberculosis and five mutants derived from H37Rv resistant to INH. Seventeen of 33 resistant strains (51 %) had katG mutations with 12 of the 17 strains having the most common KatG Ser315Thr mutation. Three of the 17 strains with the KatG 315 mutation had an additional mutation in the inhA promoter and were resistant to a high level of INH. Seventeen of the 33 INH-resistant strains (51 %) had inhA mutations. The most common inhA promoter mutation was -15C-->T and was present in 13 of the 17 inhA mutations. This promoter mutation occurred alone without katG mutations and was associated with a low level of INH and ethionamide resistance. However, other inhA mutations were associated with katG mutations. No mutations were found in the ndh gene. Three of 33 strains (9 %) had no mutations in katG, inhA or ndh, indicating that their resistance was due to a new mechanism of resistance. Detection of the KatG Ser315Thr mutation and the -15C-->T inhA mutation accounted for 76 % (25/33) of the INH-resistant strains and should be useful for rapid detection of INH-resistant strains by molecular tests.
 ...
PMID:Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA. 1703 Sep 12

Isoniazid (INH) and rifampin (RIF) are two of the most important antituberculosis drugs, and resistance to both of these drugs can often result in treatment failure and fatal clinical outcome. Resistance to these two first-line drugs is most often attributed to mutations in the katG, inhA, and rpoB genes. Historically, the identification and testing of the susceptibility of Mycobacterium tuberculosis complex (MTBC) strains takes weeks to complete. Rapid detection of resistance using the PCR-based Genotype MTBDR assay (Hain Lifescience GmbH, Nehren, Germany) has the potential to significantly shorten the turnaround time from specimen receipt to reporting of results of susceptibility testing. Therefore, the aim of the present study was to determine (i) the sensitivity and accuracy of the Genotype MTBDR assay for the detection of MTBC strains and (ii) the ability of the assay to detect the presence of INH and RIF resistance-associated mutations in katG and rpoB from samples taken directly from smear-positive clinical specimens. The results were compared with those obtained with the reference BACTEC 460TB system combined with standard DNA sequencing analysis methods for katG, inhA, and rpoB. A total of 92 drug-resistant and 51 pansusceptible smear-positive specimens were included in the study. The Genotype MTBDR assay accurately and rapidly detected MTBC strains in 94.4% of the 143 specimens and showed a sensitivity of 94.4% for katG and 90.9% for rpoB when used directly on smear-positive specimens. The assay correctly identified INH resistance in 48 (84.2%) of the 57 specimens containing strains with resistance to high levels of INH (0.4 microg/ml) and RIF resistance in 25 (96.2%) of the 26 specimens containing RIF-resistant strains.
 ...
PMID:Use of smear-positive samples to assess the PCR-based genotype MTBDR assay for rapid, direct detection of the Mycobacterium tuberculosis complex as well as its resistance to isoniazid and rifampin. 1703 88

Following identification of large genomic polymorphisms in a previous study, a polymerase chain reaction and sequencing strategy was used to identify single nucleotide polymorphisms (SNPs) in 25 genes in the sheep (S) and cattle (C) strains of Mycobacterium avium subsp. paratuberculosis (M. a. paratuberculosis) and between M. a. paratuberculosis and M. a. avium. From 12,117 bp of sequence representing 26 loci across 25 genes, 11 SNPs were identified between the S and C strains in eight genes: hsp65, sodA, dnaA, dnaN, recF, gyrB, inhA, and pks8. An in silico comparison of these M. a. paratuberculosis sequences and the M. a. avium 104 genome revealed 86 SNPs, which corresponded well with similar studies of SNPs in the M. avium complex.
 ...
PMID:Genomic diversity in Mycobacterium avium: single nucleotide polymorphisms between the S and C strains of M. avium subsp. paratuberculosis and with M. a. avium. 1704 6

We developed a DNA sequencing-based method to detect mutations in the genome of drug-resistant Mycobacterium tuberculosis. Drug resistance in M. tuberculosis is caused by mutations in restricted regions of the genome. Eight genome regions associated with drug resistance, including rpoB for rifampin (RIF), katG and the mabA (fabG1)-inhA promoter for isoniazid (INH), embB for ethambutol (EMB), pncA for pyrazinamide (PZA), rpsL and rrs for streptomycin (STR), and gyrA for levofloxacin, were amplified simultaneously by PCR, and the DNA sequences were determined. It took 6.5 h to complete all procedures. Among the 138 clinical isolates tested, 55 were resistant to at least one drug. Thirty-four of 38 INH-resistant isolates (89.5%), 28 of 28 RIF-resistant isolates (100%), 15 of 18 EMB-resistant isolates (83.3%), 18 of 30 STR-resistant isolates (60%), and 17 of 17 PZA-resistant isolates (100%) had mutations related to specific drug resistance. Eighteen of these mutations had not been reported previously. These novel mutations include one in rpoB, eight in katG, one in the mabA-inhA regulatory region, two in embB, five in pncA, and one in rrs. Escherichia coli isolates expressing individually five of the eight katG mutations showed loss of catalase and INH oxidation activities, and isolates carrying any of the five pncA mutations showed no pyrazinamidase activity, indicating that these mutations are associated with INH and PZA resistance, respectively. Our sequencing-based method was also useful for testing sputa from tuberculosis patients and for screening of mutations in Mycobacterium bovis. In conclusion, our new method is useful for rapid detection of multiple-drug-resistant M. tuberculosis and for identifying novel mutations in drug-resistant M. tuberculosis.
 ...
PMID:Detection of multidrug resistance in Mycobacterium tuberculosis. 1710 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>