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)

From a collection of 367 isolates of Mycobacterium tuberculosis from patients in New York City in 1994, 45 isolates (12.3%) were resistant in vitro to 2 micrograms or more of streptomycin (SM) per ml. We further evaluated these isolates for levels of SM resistance and for mutations previously associated with resistance in the rpsL (S12 ribosomal protein) gene and the rrs (16S rRNA)-coding region. Twenty-four isolates, representing nine distinct patterns of susceptibility to antituberculosis drugs, were resistant to 500 micrograms of SM per ml and shared a common point mutation at nucleotide 128 in the rpsL gene. This mutation, which substitutes lysine for arginine in the S12 ribosomal binding protein, was not present in isolates with low-level SM resistance or in SM-susceptible control isolates. Among 20 isolates with low-level SM resistance, one possessed a substitution (C-->G865) in the 912 loop of the rrs gene. No mutations in the 530 loop of the rrs coding region were detected, suggesting the presence of an alternative SM resistance mechanism in 19 isolates. Single-strand conformation polymorphisms of mutants were readily detected by a nonradioactive gel screen.
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PMID:Characterization of streptomycin resistance mechanisms among Mycobacterium tuberculosis isolates from patients in New York City. 872 63

The U.S.-Japan Medical Cooperative Program has been started in 1965 and Tuberculosis Panel is one of the most important field of the programs. In this lecture, the recent advances in the basic studies on tuberculosis researches which were reported in Tuberculosis panel of the program were summarized. The host defence mechanisms against M. tuberculosis infection were the most important subject. The role of Th1-mediated cytokins such as IL-2, IFN gamma and TNF beta in the host-defence mechanism against mycobacterial infection was extensively discussed. Bcg gene of the mice is the example case for the genetic background of host against mycobacterial infection. The virulence factor, however of M. tuberculosis is still unknown. The technique of molecular biology was applied to the diagnosis of tuberculosis. The PCR and RFLP methods are the useful strategies for the rapid diagnosis and analysis of the mode of infection with M. tuberculosis. The development of detection techniques of drug-resistant tubercle bacilli is also urgently required. Another approach by molecular biology to tuberculosis research is the cloning of gene of tuberculin protein and the production recombinant protein of M. tuberculosis. The amino acid sequences of several proteins have been determined and their immunological properties of recombinant proteins were investigated. The immunological functions of lipid fractions of tubercle bacilli such as cord factor (TDM) and lipoarabinomannan (LAM) have been described. Especially the immunomodulating activities and the role of TDM as diagnostic antigen in the tuberculosis patients were described. The adjuvant activity of mycobacterial cell wall was well established and the minimum structural requirement was reported to be N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). The several MDP derivatives were selected as the cytokine inducers. Especially MDP-Lys (L18) was widely used as drug for the increasing the number of white blood cells and platelets in cancer patients. The effectiveness of MDP derivatives on the stimulating of mucosal immunity was also recently reported. The preventing activities of virus infection and cancer metastasis of MDP derivatives were shown in mice models.
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PMID:[Basic studies on tuberculosis and tubercle bacilli in U.S.-Japan medical cooperative program tuberculosis panel]. 880 64

The trehalose-P synthase was purified to near homogeneity from the cytoplasmic fraction of Mycobacterium smegmatis. At the final stage of purification, the enzyme preparation showed one major band of 59 kDa on SDS gels. The 59 kDa band became labeled with N3-UDP[32P]-glucose, and this labeling was inhibited in a concentration-dependent manner by either unlabeled UDP-glucose or GDP-glucose. The native enzyme also had a molecular weight of about 60 kDa by gel filtration, indicating that the active enzyme is a monomer. The 59 kDa protein was subjected to endoproteinase Lys-C digestion, and three peptides isolated by HPLC were sequenced. The sequences of 56 amino acids in these three peptides showed 60% identity to the trehalose-P synthases of Saccharomyces cerevesiae and Schizosaccharomyces pombe. The purified mycobacterial enzyme catalyzed the synthesis of trehalose-P from glucose-6-P and a variety of nucleoside diphosphate glucose derivatives, depending on whether a polyanion was absent or present. Thus, UDP-glucose and GDP-glucose were the best glucosyl donors, but maximum activity with UDP-glucose required the presence of a polyanion such as heparin, whereas activity with GDP-glucose was relatively independent of polyanion. The presence of heparin in the incubation mixture increased the affinity of the enzyme for UDP-glucose by a factor of 100, or more. However, the affinity for GDP-glucose was only twofold better in the presence of heparin. The purified synthase also utilized ADP-glucose and CDP-glucose, but the K(m) for these glucosyl donors was quite high even in the presence of polyanion. The effect of heparin on UDP-glucose activity was dose-dependent and maximum at about 1-2 micrograms of heparin/incubation. However, the size of the heparin molecule (i.e., the number of monosaccharide residues) was critical for activation, and only those heparins with 18 or more monosaccharide units were effective in stimulating activity.
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PMID:Trehalose-P synthase of mycobacteria: its substrate specificity is affected by polyanions. 884 10

Diaminopimelate (DAP) is a unique metabolite used for both the biosynthesis of lysine in bacteria and the construction of the peptidoglycan of many species of bacteria, including mycobacteria. DAP is synthesized by bacteria as part of the aspartate amino acid family, which includes methionine, threonine, isoleucine, and lysine. Aspartokinase, the first enzyme in this pathway, is encoded by the ask gene in mycobacteria. Previous attempts to disrupt this gene in Mycobacterium smegmatis were unsuccessful, even when the cells were supplied with all the members of the aspartate family, suggesting that unlike other bacteria, mycobacteria may have an absolute requirement for this pathway even when growing in rich medium containing DAP. The purpose of this study was to determine if the ask gene and the aspartate pathway are essential to M. smegmatis. This study describes a test for gene essentiality in mycobacteria, utilizing a counterselectable marker (streptomycin resistance) in conjunction with a specially constructed merodiploid strain. We have used this system to show that the ask gene could not be disrupted in wild-type M. smegmatis, using selective rich medium supplemented with DAP unless there was an extra copy of ask provided elsewhere in the chromosome. Disruption of ask was also possible in a lysine auxotroph incapable of converting DAP to lysine. The ask mutant, mc21278 (ask1::aph), exhibits multiple auxotrophy (Met-, Thr-, DAP-, and Lys-) and is complemented by the ask gene. This is the first description of DAP auxotrophy in mycobacteria. The ask mutant lyses when deprived of DAP in culture, a characteristic which can be exploited for the reproducible preparation of protoplasts and mycobacterial extracts. The evidence presented here indicates that the aspartate pathway is essential to M. smegmatis and that DAP is the essential product of this pathway.
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PMID:Biosynthesis of diaminopimelate, the precursor of lysine and a component of peptidoglycan, is an essential function of Mycobacterium smegmatis. 893 6

Diaminopimelate (DAP) is used by bacteria for the synthesis of lysine. In many species of bacteria, including mycobacteria, DAP is also used for peptidoglycan biosynthesis. In this report we describe the cloning of the dapB gene encoding dihydrodipicolinate reductase (DHPR), which catalyzes a key branch point reaction in the bacterial DAP biosynthetic pathway, from Mycobacterium tuberculosis. Analyses of the DapB proteins from different bacterial species suggest that two different classes of DHPR enzymes may exist in bacteria.
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PMID:Cloning of the dapB gene, encoding dihydrodipicolinate reductase, from Mycobacterium tuberculosis. 909 82

Mutagenesis of the host immune system has helped identify response pathways necessary to combat tuberculosis. Several such pathways may function as activators of a common protective gene: inducible nitric oxide synthase (NOS2). Here we provide direct evidence for this gene controlling primary Mycobacterium tuberculosis infection using mice homozygous for a disrupted NOS2 allele. NOS2(-/-) mice proved highly susceptible, resembling wild-type littermates immunosuppressed by high-dose glucocorticoids, and allowed Mycobacterium tuberculosis to replicate faster in the lungs than reported for other gene-deficient hosts. Susceptibility appeared to be independent of the only known naturally inherited antimicrobial locus, NRAMP1. Progression of chronic tuberculosis in wild-type mice was accelerated by specifically inhibiting NOS2 via administration of N6-(1-iminoethyl)-L-lysine. Together these findings identify NOS2 as a critical host gene for tuberculostasis.
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PMID:Identification of nitric oxide synthase as a protective locus against tuberculosis. 914 22

Mycobacterium tuberculosis secretes several proteins into the extracellular environment, some of which are restricted to the M. tuberculosis complex. One of these antigens is MPT64. Recently, the authors showed that native as well as recombinant MPT64 is able to distinguish between an M. tuberculosis infection and a BCG Danish 1331 vaccination. Improved distinction between tuberculin purified protein derivative (PPD) sensitivity conferred by an M. tuberculosis infection and that induced by a BCG vaccination or infection with environmental mycobacteria would be useful in the control of tuberculosis. In this study, the authors report the mapping and characterization of a Dth-inducing epitope by the use of synthetic peptides in guinea-pigs vaccinated with BCG Danish 1331 or Tokyo. Studies with overlapping synthetic peptides have pinpointed the biological activity to a single Dth-inducing epitope at the carboxyterminal region of MPT64 consisting of 15 residues between amino acids Gly-173 and Ala-187, the core epitope (CE15). A fine mapping using truncated versions of CE15 indicates the epitope is restricted to 13 residues between amino acids Val-174 to Glu-186. However, the optimal Dth reactivity is obtained by CE15. Different modifications of CE15 revealed that a lysine tree construction improves the skin reactivity to a maximum level approaching that of the reactivity to tuberculin PPD.
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PMID:Characterization of the delayed type hypersensitivity-inducing epitope of MPT64 from Mycobacterium tuberculosis. 916 93

The relationship between streptomycin (SM) susceptibility and rpsL mutations of Mycobacterium tuberculosis strains was studied. Of 18 clinically isolated SM-resistant M.tuberculosis strains, mutation was suspected in 9 strains (50%) with SM MICs of > or = 256 micrograms/ml by PCR-single strand conformation polymorphism targeting rpsL gene. On the other hand, using PCR-direct sequence method, amino acid substitution caused by single nucleotide point mutation in rpsL gene was demonstrated in 11 out of 18 strains (61%). The same amino acid substitution at codon 43 (Lys-->Arg) was observed in all 11 strains with SM MICs of > or = 256 micrograms/ml. In addition, PCR products obtained from these 11 strains could not be cut by a restriction enzyme, Mbo II, while H37Rv strain and the other 32 strains with SM MICs of < 256 micrograms/ml were cut into 2 fragments. In conclusion, our results suggest that highly SM-resistant M.tuberculosis strains with MICs of > or = 256 micrograms/ml could be rapidly and easily detected by the restriction enzymatic method.
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PMID:[Relationship between streptomycin susceptibility and rpsL mutations of Mycobacterium tuberculosis strains]. 936 10

The increase in multidrug-resistant tuberculosis and high mortality among those co-infected with HIV-1 necessitates new therapeutic approaches directed at Mycobacterium tuberculosis. We hypothesized that a dominant-negative mutation in the DNA-dependent RNA polymerase gene would inhibit transcription of all genes by blocking access of the wild-type enzyme to promoters. An evolutionarily invariant lysine was substituted with arginine by site-directed mutagenesis in the rpoB gene. The dominant-negative rpoB gene product inhibited a transposon-derived kanamycin-resistance gene in both M. smegmatis and M. tuberculosis H37Rv, leading to growth inhibition of the mycobacteria on solid media containing kanamycin. The dominant-negative mutant rpoB gene is a potential suicide gene especially for the treatment of multidrug-resistant tuberculosis once a delivery strategy is also developed.
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PMID:Development of a suicide gene as a novel approach to killing Mycobacterium tuberculosis. 941 85

Conjugates of a carbacephalosporin with hydroxamate, spermexatol, N alpha,N epsilon-bis(2,3-dihydroxybenzoyl)-L-lysine, mixed catecholate/hydroxamate and cyanuric acid-based siderophores were investigated for their potential to promote growth of siderophore indicator strains of Gram-negative and Gram-positive bacteria under iron depleted conditions, for their antibacterial activity and for their ability to use iron transport pathways to penetrate the Gram-negative bacterial outer membrane. The selective growth promotion of enterobacterial and pseudomonas strains by hydroxamate, spermexatol and mixed catecholate-hydroxamate siderophore-based conjugates bearing a L- or D-amino acid spacer was correlated with TonB dependent uptake routes. The preferred outer membrane siderophore receptor used in Escherichia coli was found to be Fiu, followed by Cir. Antagonistic effects of siderophores administered with the conjugates to determine antibacterial activity confirmed the active transport of conjugates via siderophore receptors. All of the conjugates were still able to diffuse through the porin proteins OmpC and OmpF. Nevertheless, strong inhibition of E. coli and Pseudomones aeruginosa outer membrane mutants DC2 and K799/61 compared to the parent strains indicated inefficient penetrability of all types of conjugates tested. Mycobacterium smegmatis SG 987 was able to use all of the siderophore-cephalosporin conjugates as growth promotors. Consequently there was no growth inhibition of this strain.
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PMID:Selective growth promotion and growth inhibition of gram-negative and gram-positive bacteria by synthetic siderophore-beta-lactam conjugates. 945 Mar 13


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