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

The target of the potent antituberculosis drug isoniazid was investigated in Mycobacterium aurum A+, against which isoniazid has an MIC (the minimum concentration required to give growth inhibition) of 0.3 microgram/ml. Mycolic acid biosynthesis, measured by the incorporation of label from [1-14C]acetate into mycolic acids, was inhibited differentially by isoniazid in cell-wall preparations of M. aurum A+. Thus at an isoniazid concentration of 1 microgram/ml, mycolic acid biosynthesis was inhibited by 80% but concomitant biosynthesis of non-hydroxylated fatty acids was inhibited by only 15%. Three lines of evidence identified 24:1 cis-5 elongase as the primary isoniazid target. First, 24:1 cis-5 did not restore isoniazid-inhibited mycolic acid biosynthetic activity in a crude cell-wall preparation, suggesting that the drug acts after the formation of the delta-5 double bond. Secondly, a 24:1 cis-5 elongase assay in which the product is mycolic acid is completely inhibited by isoniazid. Finally, the only intermediates that accumulate as a result of the addition of isoniazid are acids of 24 carbons. Both 24:0 and 24:1 are observed in a similar ratio whether or not isoniazid is present, even though concomitant mycolic acid biosynthesis is inhibited by isoniazid. These results are consistent with studies of the M. tuberculosis InhA protein by Dessen, Quemard, Blanchard, Jacobs and Sacchettini [(1995) Science 267, 1638-1641].
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PMID:Determination of the primary target for isoniazid in mycobacterial mycolic acid biosynthesis with Mycobacterium aurum A+. 880 32

In vitro antimicrobial activities of the benzoxazinorifamycin derivative KRM-1648 (KRM) against 50 strains of Mycobacterium tuberculosis isolated from patients with mainly intractable pulmonary tuberculosis were studied. MIC90 values of KRM, rifabutin (RBT) and rifampicin (RFP) for RFP-sensitive strains (27 strains; defined as those with MICRFP values of < 1.56 micrograms/ml) were 0.013, 0.1 and 0.4 micrograms/ml, respectively, when determined by the agar dilution method using 7H11 medium. MIC90 values of KRM, RBT, and RFP for RFP-resistant strains (23 strains; defined as those having MICRFP values of > or = 1.56 micrograms/ml) were 100, 12.5 and > 100 micrograms/ml, respectively. MICs of KRM against 50 clinical isolates of M. tuberculosis distributed over a much lower range than those of RFP. KRM showed more potent antimicrobial activity than RBT against the organisms with low MIC values (< or = 1.56 micrograms/ml), while it was not so active as RBT against the organisms with high MIC values (> or = 3.13 micrograms/ml). Cross-resistance between KRM and RFP or RBT was observed for M. tuberculosis.
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PMID:[In vitro activities of benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis]. 883 Nov 91

To characterize mechanisms of resistance to fluoroquinolones by Mycobacterium tuberculosis, mutants of strain H37Ra were selected in vitro with ofloxacin. Their quinolone resistance-determining regions for gyrA and gyrB were amplified and sequenced to identify mutations in gyrase A or B. Three types of mutants were obtained: (i) one mutant (TKp1) had no mutations in gyrA or gyrB; (ii) mutants that had single missense mutations in gyrA, and (iii) mutants that had two missense mutations resulting in either two altered gyrase A residues or an altered residue in both gyrases A and B. The TKp1 mutant had slightly reduced levels of uptake of [14C]norfloxacin, which was associated with two- to fourfold increases in the MICs of ofloxacin, ciprofloxacin, and sparfloxacin. Gyrase mutations caused a much greater increase in the MICs of fluoroquinolones. For mutants with single gyrA mutations, the increases in the MICs were 4- to 16-fold, and for mutants with double gyrase mutations, the MICs were increased 32-fold or more compared with those for the parent. A gyrA mutation in TKp1 secondary mutants was associated with 32- to 128-fold increases in the MICs of ofloxacin and ciprofloxacin compared with the MICs for H37Ra and an eight-fold increase in the MIC of sparfloxacin. Sparfloxacin was the most active fluoroquinolone tested. No sparfloxacin-resistant single-step mutants were selected at concentrations of > 2.5 micrograms/ml, and high-level resistance (i.e., MIC, > and = 5 micrograms/ml) was associated with two gyrase mutations. Mutations in gyrB and possibly altered levels of intracellular accumulation of drug are two additional mechanisms that may be used by M. tuberculosis in the development of fluoroquinolone resistance. Because sparfloxacin is more active in vitro and selection of resistance appears to be less likely to occur, it may have important advantage over ofloxacin or ciprofloxacin for the treatment of tuberculosis.
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PMID:Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra. 884 79

Susceptibilities to the new semisynthetic tetracycline (Tet) compounds N,N-dimethylglycylamido-minocycline (DMG-MINO) and N,N-dimethylglycylamido-6-demethyl-6-deoxytetracycline (DMG-DMDOT) were compared with those to doxycycline, minocycline, and Tet for 198 Tet-resistant (Tetr) and 33 Tet-susceptible (Tets) clinical isolates of rapidly growing mycobacteria (RGM) including the Mycobacterium fortuitum group, Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium mucogenicum and 68 isolates belonging to six taxa of Nocardia spp. All Tetr RGM were highly susceptible to the glycylcyclines. The MICs at which 50 and 90% of isolates are inhibited were < or = 0.125 and < or = 0.25 microgram/ml, respectively, for DMG-DMDOT and < or = 0.25 and 1 microgram/ml, respectively, for DMG-MINO. The MIC of DMG-DMDOT at which 50% of Tetr strains are inhibited was the same as that for Tets strains for each of the four taxa of RGM. The new agents were less active against Nocardia spp. MICs of DMG-DMDOT were comparable to those of minocycline except for the MICs for Nocardia brasiliensis sensu stricto, the new taxon Nocardia pseudobrasiliensis, and some isolates of Nocardia nova, against which they were four- to eightfold more active. The MICs of DMG-DMDOT were consistently lower than those of DMG-MINO for RGM. This class of drugs offers exciting therapeutic potential for RGM and for selected species of Nocardia.
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PMID:Activities of the glycylcyclines N,N-dimethylglycylamido-minocycline and N,N-dimethylglycylamido-6-demethyl-6-deoxytetracycline against Nocardia spp. and tetracycline-resistant isolates of rapidly growing mycobacteria. 884 43

Using 39 clinical isolates of Mycobacterium strains with a broad range of susceptibility to rifampicin, we examined the relationship between the degree of resistance to rifampicin and mutational sites of the rpoB gene. All rifampicin-resistant strains had missense mutations. Twenty strains (95%) had a mutation in the cluster I region, which has also been reported in Escherichia coli [Jin and Gross (1988) J. Mol. Biol. 202, 45-58], and the remaining one strain had a mutation at codon 381 [Ala-->Val] in the N-terminal region, which has not been reported in E. coli. Among 18 rifampicin-susceptible strains, two had a mutation in the cluster I region and the other three strains had a mutation in the cluster III region. The mutations at codons 513 (5%), 526 (33%) or 531 (43%) in the cluster I region led to high level resistance to rifampicin (50 micrograms ml-1 < or = MIC). The mutations at the other sites, in the cluster III region (codons 679 or 687) and even in the cluster I region (codon 514, 521, or 533), showed low level (MIC = 12.5 micrograms ml-1) or no (MIC < 0.39 microgram ml-1) resistance to rifampicin. These results suggest that mutations in the rpoB gene are, mostly, but not necessarily, associated with rifampicin resistance of M. tuberculosis, and the sites of mutations on the rpoB gene will affect the level of resistance to rifampicin.
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PMID:Rifampicin resistance and mutation of the rpoB gene in Mycobacterium tuberculosis. 887 Feb 58

We determined the nucleotide sequence of a 6-kb DNA region harboring the recF, orf192, gyrB, and gyrA genes from Mycobacterium smegmatis mc(2)155. The amino acid sequences deduced from gyrA and gyrB displayed 89 and 86% identity, respectively, with the DNA gyrase from Mycobacterium tuberculosis, and 67 and 65% identity, respectively, with that from Streptomyces coelicolor. An open reading frame encoding the C-terminal region of the M. smegmatis RecF polypeptide was found upstream from gyrB and was 57% identical to the open reading frame encoding the C-terminal region of the S. coelicolor RecF protein. The gene orf192 was identified between recF and gyrB and was 39% identical to orf191 found in S. coelicolor in the recF-gyrB region. The M. smegmatis DNA gyrase, which was purified by affinity chromatography on novobiocin-Sepharose, consisted of two polypeptides with apparent molecular masses of 98 and 80 kDa. Determination of the N-terminal amino acid sequence of the B subunit confirmed GTG as the start codon in gyrB. Analysis of the supercoiling activity of the enzyme indicated that the M. smegmatis DNA gyrase was characterized by a specific activity equivalent to that of the Escherichia coli DNA gyrase. Inhibition of this activity by 4-quinolones was investigated by determining the 50% inhibitory concentrations (IC50S) of nalidixic acid, ofloxacin, and ciprofloxacin. The results indicated that the inhibitory activities of these drugs against the M. smegmatis DNA gyrase were markedly lower than those previously reported for the E. coli DNA gyrase. The results also suggested that the higher levels of activity of ofloxacin and ciprofloxacin against M. smegmatis (MICs, 0.5 to 1 microgram/ml), in contrast to that of nalidixic acid (MIC, 256 micrograms/ml), could be related to the higher inhibitory activities of fluoroquinolones against the DNA gyrase from this species (IC50S, 7 to 14 micrograms/ml) compared with that of nalidixic acid (IC50, 1,400 micrograms/ml).
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PMID:Sequence analysis, purification, and study of inhibition by 4-quinolones of the DNA gyrase from Mycobacterium smegmatis. 887 80

Azithromycin exhibited in-vitro activity against 20 clinical isolates of Mycobacterium avium complex for which the MIC90 was 32 mg/L and 22 clinical isolates of other mycobacteria but showed no activity against 20 isolates of Mycobacterium tuberculosis (MIC90 > 128 mg/L) nor against the single isolate of Mycobacterium marinum tested (MIC 128 mg/L). These results suggest that the drug may prove useful for the prophylaxis and treatment of infections due to non-tuberculous mycobacteria, including M. avium complex in patients with AIDS.
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PMID:Comparative activity of azithromycin against clinical isolates of mycobacteria. 888 27

Isoniazid (INH), one of the most effective antimycobacterial drugs, specifically inhibits, at an early stage of its action, the biosynthesis of mycolic acids, specific mycobacterial lipids which play a central role in the cell envelope architecture of mycobacteria. In the present study, the consequences of the action of INH on the cell morphology of Mycobacterium tuberculosis and Mycobacterium aurum were examined. Electron microscopy was used to observe bacilli which were previously treated with either subinhibitory concentrations of INH or the MIC of the drug, leading to a decrease of 20 to 35% (by weight) of their mycolic acid contents. The earlier effect of INH on the ultrastructure of mycobacteria, as revealed by negative staining of bacilli, was the alteration of the bacterial poles; this event was observed prior to the bacteriostatic action of the drug and was accompanied by a release of material from the poles into the extracellular medium. In a later stage of the drug's action, cell deformation occurred and more extracellular material was seen. The material released following the action of the drug on susceptible mycobacterial cells was identified as being almost exclusively composed of proteins. Labeling of amino acids with 35S prior to and during the action of INH on M. aurum and subsequent analysis of the labeled proteins led to the conclusion that they consisted of secreted proteins which were up to 20-fold oversecreted in the presence of the drug. Competitive enzyme-linked immunosorbent assay with the secreted 45/47-kDa antigen complex of M. tuberculosis demonstrated up to 20-fold oversecretion of these proteins. Taken together, the production of oversecreted proteins following the decrease of the cell envelope mycolate content by INH strongly suggests that mycolic acids may act as a barrier in the export of proteins secreted by mycobacteria.
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PMID:Effects of isoniazid on ultrastructure of Mycobacterium aurum and Mycobacterium tuberculosis and on production of secreted proteins. 891 47

A series of N-(2-hydroxyethyl)-1,2-benzisothiazol-3(2H)-one and -thione carbamic esters have been synthesised and tested against Mycobacterium avium strains. The MIC values determined by the radiometric broth dilution method were between 2 and 8 micrograms/mliters for the benzisothiazolthione derivatives and between 16 and 32 micrograms/mliters or higher for the corresponding benzisothiazolone derivatives.
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PMID:In vitro anti-Mycobacterium avium activity of N-(2-hydroxyethyl)-1,2-benzisothiazol-3(2H)-one and -thione carbamic esters. 891 5

A series of 4-alkylthiopyridine-2-carbothioamides have been prepared and evaluated in vitro for antimicrobial activity. Chemical structures have been demonstrated by IR and 1H NMR data and by elemental analysis. The antimycobacterial activity of these compounds against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium, and Mycobacterium fortuitum, and the antifungal activity against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Trichosporon beigelii, Trichophyton mentagrophytes, Aspergillus fumigatus, and Absidia corymbifera were determined by the MIC values. Compounds 3 exhibit good antimycobacterial activity compared to isoniazide. A moderate antifungal activity was observed against T. mentagrophytes. Activity is influenced by hydrophobicity of the alkyl group.
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PMID:Research on antifungal and antimycobacterial agents. Synthesis and activity of 4-alkylthiopyridine-2-carbothioamides. 893 45


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