Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

DL-S-n-(3-(4-acetyl)-2-oxo-5-oxazolidynyl methyl) acetamide (DuP-721) is an orally active representative of the oxazolidinone series of antimicrobials. At concentrations ranging from 1.5 to 4 micrograms/ml, DuP-721 inhibited equally the strains of Mycobacterium tuberculosis susceptible and resistant to conventional antituberculosis drugs. DuP-721 inhibited M. gordonae and M. fortuitum at 3.9 micrograms/ml, M. kansasii at 1.95, and M. scrofulaceum at 15.6 micrograms/ml. It was not active against M. avium and M. intracellulare at concentrations of 250 micrograms/ml. The inhibition of the metabolism of M. tuberculosis as indicated by the liquid scintillation radiometric method was 56% at fourfold the minimum inhibitory concentration (MIC) of DuP-721 that compared well to that of the fourfold MIC concentrations of rifampicin and isoniazid. The in vitro activity of DuP-721 was not affected by reducing the pH from 6.8 to 5.5. In mice infected with M. tuberculosis, the 50% effective dose (ED50) for DuP-721 was 13.2 mg/kg when administered daily beginning 4 hr postinfection for 17 days. The ED50 was 71.8 mg/kg when DuP-721 was administered only on days 11 and 12 postinfection. A 100% survival rate was obtained at 50 and 160 mg/kg when DuP-721 was administered daily for 17 days, and only on days 11 and 12 after the infection, respectively. The increase in the survival time by DuP-721 at 100 mg/kg (eightfold the ED50 dose) when administered daily for 17 days beginning 4 hr after infection was inferior to that by eightfold the ED50 dose of rifampicin and isoniazid administered on days 11 and 12 postinfection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxazolidinones, a new class of synthetic antituberculosis agent. In vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis. 180 33

Using incident light energy of about 76 mW.cm-2 in a dye-sensitized photooxidation reaction, we have investigated the possible involvement of one or both of the histidine residues in the catalytic activity of adenylate kinase (ATP:AMP phosphotransferase) of Mycobacterium marinum. We have done this by investigating the kinetics of photochemical inactivation of the enzyme. At pH 7.4, the kinetics of photoinactivation are biphasic with two different pseudo-first-order rate constants. Adenosine 5'-pentaphospho 5'-adenosine (Ap5A), ATP and, to some extent, AMP, all gave protection to the enzyme from inactivation. Amino-acid analysis of the photoinactivated enzyme indicated the loss of the two histidine residues. This, and the fact that photoinactivation occurred faster at alkaline compared to acidic pH, indicated the involvement of the histidine residues in the catalytic activity. A mathematical model is developed which assumes that both histidine residues are required for maximal catalytic activity: one is located peripherally, is exposed, and therefore is readily photooxidized (pseudo-first-order rate constant, k1 = 1.3.10(-2)s-1), while the other is located at the active site, involved in substrate-binding and is shielded (pseudo-first-order rate constant, k2 = 2.9.10(-4)s-1). However, this shielded histidine could be exposed and made more accessible to photooxidation either by raising the pH above 10, or alternatively, by the addition of 8 M acetamide (or 6 M guanidine). Under these conditions, which apparently cause unfolding of the protein molecule, the kinetics of photoinactivation change from biphasic to monophasic, suggesting that both histidine residues are equally exposed and are photooxidized at the same rate. Unlike the enzyme from M. marinum, adenylate kinase from bovine heart mitochondria shows monophasic kinetics of photoinactivation at pH 7.4, suggesting that only one of the six histidine residues is essential for catalytic activity, or if more than one, then they all must be equally exposed. Further, ATP, AMP or Ap5A did not provide protection against photoinactivation, suggesting that the histidine residue(s) involved in the catalytic activity must remain exposed after the substrates bind at the active site of the mitochondrial enzyme.
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PMID:A kinetic study of the photochemical inactivation of adenylate kinases of Mycobacterium marinum and bovine heart mitochondria. 215 72

Mycobacterium fortuitum subspecies acetamidolyticum is a new subspecies of M. fortuitum and has an intermediate growth rate. It is a nonphotochromogenic mycobacterium. It does not utilize glutamate but utilizes acetamide as a simultaneous nitrogen and carbon source. It is able to utilize acetate, malate, pyruvate, fumarate, glucose, fructose, and n-propanol as the sole sources of carbon in the presence of ammoniacal nitrogen, but does not utilize them in the presence of glutamate-nitrogen. It is easily differentiated from all rapidly growing mycobacteria by its inability to utilize glutamate as a simultaneous nitrogen and carbon source, and from all slowly growing mycobacteria by its capacity to utilize acetamide as a simultaneous nitrogen and carbon source. Its mycolic acid pattern is different from that of M. fortuitum. However, its deoxyribonucleic acid showed 94% relatedness with that of M. fortuitum. In view of the above findings, it has been designated as a new subspecies of M. fortuitum. The organism was isolated from sputum of a 56-year-old patient with lung disease and is considered to be a lung pathogen. The type strain is ATCC 35931 (NCH E11620).
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PMID:Mycobacterium fortuitum subspecies acetamidolyticum, a new subspecies of Mycobacterium fortuitum. 371 61

Oxazolidinones make up a relatively new class of antimicrobial agents which possess a unique mechanism of bacterial protein synthesis inhibition. U-100592 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]- phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and U-100766 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]- 2-oxo-5-oxazolidinyl]methyl]-acetamide are novel oxazolidinone analogs from a directed chemical modification program. MICs were determined for a variety of bacterial clinical isolates; the respective MICs of U-100592 and U-100766 at which 90% of isolates are inhibited were as follows: methicillin-susceptible Staphylococcus aureus, 4 and 4 micrograms/ml; methicillin-resistant S. aureus, 4 and 4 micrograms/ml; methicillin-susceptible Staphylococcus epidermidis, 2 and 2 micrograms/ml; methicillin-resistant S. epidermidis, 1 and 2 micrograms/ml; Enterococcus faecalis, 2 and 4 micrograms/ml; Enterococcus faecium, 2 and 4 micrograms/ml; Streptococcus pyogenes, 1 and 2 micrograms/ml; Streptococcus pneumoniae, 0.50 and 1 microgram/ml; Corynebacterium spp., 0.50 and 0.50 micrograms/ml; Moraxella catarrhalis, 4 and 4 micrograms/ml; Listeria monocytogenes, 8 and 2 micrograms/ml; and Bacteroides fragilis, 16 and 4 micrograms/ml. Most strains of Mycobacterium tuberculosis and the gram-positive anaerobes were inhibited in the range of 0.50 to 2 micrograms/ml. Enterococcal strains resistant to vancomycin (VanA, VanB, and VanC resistance phenotypes), pneumococcal strains resistant to penicillin, and M. tuberculosis strains resistant to common antitubercular agents (isoniazid, streptomycin, rifampin, ethionamide, and ethambutol) were not cross-resistant to the oxazolidinones. The presence of 10, 20, and 40% pooled human serum did not affect the antibacterial activities of the oxazolidinones. Time-kill studies demonstrated a bacteriostatic effect of the analogs against staphylococci and enterococci but a bactericidal effect against streptococci. The spontaneous mutation frequencies of S. aureus ATCC 29213 were <3.8 x 10(-10) and <8 x 10(-11) for U-100592 and U-100766, respectively. Serial transfer of three staphylococcal and two enterococcal strains on drug gradient plates produced no evidence of rapid resistance development. Thus, these new oxazolidinone analogs demonstrated in vitro antibacterial activities against a variety of clinically important human pathogens.
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PMID:In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. 884 37

The inducible acetamidase of Mycobacterium smegmatis NCTC 8159 is expressed at high levels in the presence of a suitable inducer, such as acetamide. The gene and 1.5 kb of upstream sequence had previously been sequenced. A further 1.4 kb of upstream sequence has now been determined, containing an additional ORF on the opposite strand to the acetamidase gene. This ORF has significant homologies to genes encoding regulatory proteins involved in amidase expression in other organisms. Restriction fragments from the 4 kb region were subcloned into a promoter-probe shuttle vector to locate the approximate region of the acetamidase promoter and investigate the mechanism of regulation. An inducible promoter was found to lie in the 1.4 kb region situated 1.5 kb upstream from the acetamidase coding region. Expression of the acetamidase was studied at the protein and mRNA levels. Using immunoblotting, induction of the enzyme was demonstrated in minimal medium containing succinate plus acetamide, but not in a richer medium (Lemco broth) plus acetamide, confirming that regulation of acetamidase expression is mediated by both positive and negative control elements. After induction by acetamide, an increase above basal level could be detected after 1 h for both protein levels (using ELISA) and mRNA levels (using Northern blot analysis), indicating that control of expression is at the mRNA level. The size of the mRNA transcript detected was approximately 1.2 kb, the size of the acetamidase coding region. Since no promoter was identified immediately upstream of the coding region, this raises the possibility that a larger, primary transcript (possibly polycistronic) is cleaved to produce a stable form encoding the acetamidase protein.
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PMID:Regulation of the inducible acetamidase gene of Mycobacterium smegmatis. 924 15

Expression from a 2.3 kb region upstream of the inducible acetamidase gene from Mycobacterium smegmatis was shown to be upregulated by acetamide. A DNA fragment containing the start of the M. smegmatis hisD gene was cloned in front of the promoter, such that the antisense message was produced. When this construct was induced in vivo, the bacteria became phenotypically histidine auxotrophs; this auxotrophy was restored by histidine supplementation. Auxotrophy was not observed under non-induced conditions. Antisense mutagenesis may be useful for observing the phenotypic inactivation of specific mycobacterial genes, and an inducible system such as that described would allow the study of essential genes.
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PMID:Development and use of a conditional antisense mutagenesis system in mycobacteria. 929 33

A novel expression vector utilising the highly inducible acetamidase promoter of Mycobacterium smegmatis was constructed. High-level induction of a model antigen, the Mycobacterium leprae 35 kDa protein, was demonstrated in recombinant M. smegmatis grown in the presence of the acetamidase inducer acetamide. The recombinant protein could be simply and efficiently purified from the bacterial sonicate by virtue of a C-terminal 6-histidine tag, demonstrating that this purification strategy can be used for the mycobacteria. The histidine tag had no apparent effect on the protein conformation or immunogenicity, suggesting that the vector described may prove useful for the purification of native-like recombinant mycobacterial proteins from fast-growing mycobacterial hosts.
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PMID:An inducible expression system permitting the efficient purification of a recombinant antigen from Mycobacterium smegmatis. 980 15

Rapidly growing mycobacteria are capable of causing several clinical diseases in both immunosuppressed and immunocompetent individuals. A previously unidentified, rapidly growing mycobacterium was determined to be the causative agent of central line sepsis in a child with underlying metastatic hepatoblastoma. Four isolates of this mycobacterium, three from blood and one from the central venous catheter tip, were studied. Phenotypic characterization, HPLC and genetic analysis revealed that while this organism most closely resembled members of the Mycobacterium fortuitum complex and Mycobacterium senegalense, it differed from all previously described species. Phenotypic tests useful in differentiating this species from similar rapidly growing mycobacteria included: growth at 42 degrees C, hydrolysis of acetamide, utilization of citrate, production of arylsulfatase (3-d), acidification of D-mannitol and i-myo-inositol, and susceptibility to erythromycin, vancomycin and tobramycin. The name Mycobacterium septicum is proposed for this new species. The type strain has been deposited in Deutsche Sammlung von Mikroorganismen und Zellkulturen as DSM 44393T and in the American Type Culture Collection as strain ATCC 700731T.
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PMID:Mycobacterium septicum sp. nov., a new rapidly growing species associated with catheter-related bacteraemia. 1075 63

To begin to understand the role of Mycobacterium smegmatis dnaA in DNA replication, the dnaA gene was characterized at the genetic level. Western analyses revealed that DnaA accounts for approximately 0.18% of the total cellular protein during both the active and stationary growth periods. Expression of antisense dnaA RNA reduced viability, indicating that dnaA is an essential gene in replication. To further understand the role(s) of dnaA in replication, a conditionally expressing strain was constructed in which expression of dnaA was controlled by acetamide. Growth in the presence of 0.2% acetamide elevated the intracellular levels of DnaA and increased cell length, but did not affect viability. Visualization of DNA by fluorescence microscopy revealed that DnaA-overproducing cells were multinucleoidal, indicating a loss of synchrony between the replication and cell-division cycles. Withdrawal of acetamide resulted in the depletion of the intracellular levels of DnaA, reduced viability and gradually blocked DNA synthesis. Acetamide-starved cells were very filamentous, several times the size of the parent cells and showed either abnormal or multi-nucleoid morphology, indicating a blockage in cell-division events. The addition of acetamide to the starved cells restored their viability and shortened the lengths of their filaments back to the size of the parent cells. Thus, both increasing and decreasing the levels of DnaA have an effect on the cells, indicating that the level of DnaA is critical to the maintenance of coordination between DNA replication and cell division. It is concluded that DNA replication and cell-division processes in M. smegmatis are linked, and it is proposed that DnaA has a role in both of these processes.
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PMID:Conditional expression of Mycobacterium smegmatis dnaA, an essential DNA replication gene. 1248 Aug 93

To understand the role of Mycobacterium smegmatis ftsZ (ftsZ(smeg)) in the cell division process, the ftsZ gene was characterized at the genetic level. This study shows that ftsZ(smeg) is an essential gene in that it can only be disrupted in a merodiploid background carrying another functional copy. Expression of ftsZ(smeg) in M. smegmatis from a constitutively active mycobacterial promoter resulted in lethality whereas that from a chemically inducible acetamidase (ami) promoter led to FtsZ accumulation, filamentation and cell lysis. To further understand the roles of ftsZ in cell division a conditionally complementing ftsZ(smeg) mutant strain was constructed in which ftsZ expression is controlled by acetamide. Growth in the presence of 0.2 % acetamide increased FtsZ levels approximately 1.4-fold, but did not decrease viability or change cell length. Withdrawal of acetamide reduced FtsZ levels, decreased viability, increased cell length and eventually lysed the cells. Finally, it is shown that ftsZ(smeg) function in M. smegmatis can be replaced with the Mycobacterium tuberculosis counterpart, indicating that heterologous FtsZ(tb) can independently initiate the formation of Z-rings and catalyse the septation process. It is concluded that optimal levels of M. smegmatis FtsZ are required to sustain cell division and that the cell division initiation mechanisms are similar in mycobacteria.
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PMID:Conditional expression of Mycobacterium smegmatis ftsZ, an essential cell division gene. 1277 99


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