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)

Fifteen patients with AIDS were hospitalized on the pulmonary service during the period from 1981 to 1983. We were impressed with the frequency and severity of lung involvement in these patients and evaluated them with respect to their pulmonary manifestations of AIDS. The 13 men and two women had a mean age of 32 years. Ten were active intravenous drug abusers with a mean drug use of 8.1 years. All presented with profound weight loss, ten with nonproductive cough, and eight with significant dyspnea. Fourteen of 15 patients had Pneumocystis carinii pneumonia (PCP) at the time of our evaluation. Chest radiographs in these 14 patients showed no uniform pattern which was predictive of PCP. However, all 13 patients tested had a widened alveolar arterial oxygen gradient (mean: 59 mm Hg) which correlated well with the presence of PCP. The most common pulmonary finding in our AIDS patients was infection: 14 had PCP which was readily diagnosed by transbronchial lung biopsy in eight patients, and five patients were found to have disseminated Mycobacterium avium-intracellulare which often developed after "recovery" from PCP. Therapy for PCP with trimethoprim/sulfamethoxazole (TMP/SMZ) was unsuccessful in eight of ten patients; four of these eight TMP/SMZ failures responded to pentamidine. Mortality was 100 percent in patients who had AIDS for more than one year, and 70 percent in those less than one year. Despite some symptomatic responses to therapy for pulmonary infections, the mortality in AIDS seems to be unaffected by appropriate therapy for the pulmonary manifestations of this disease.
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PMID:Pulmonary manifestations of the acquired immunodeficiency syndrome (AIDS). 660 53

Forty-eight clinical strains of Mycobacterium fortuitum and 15 clinical strains of Mycobacterium chelonei were evaluated for susceptibility to sulfonamides, including trimethoprim-sulfamethoxazole (TMP-SMZ). Sensitivity tests were carried out with use of agar dilutions in Mueller-Hinton agar and a plate inoculum of 10(2) cfu. Thirty-six percent of the isolates of M. fortuitum were inhibited by 8 micrograms of sulfonamide/ml, and 98% were inhibited by 32 micrograms/ml. None of the isolates of M. chelonei were inhibited at these concentrations, but 73% were inhibited by 128 micrograms/ml, and 87% were inhibited by 256 micrograms/ml. Both species were highly resistant to TMP, and the combination TMP-SMZ (1:20) was no more active than was SMZ alone. The growth of M. chelonei on Mueller-Hinton agar required the addition of 10% OADC (oleic acid, albumin, dextrose, and catalase), and exact MICs were difficult to determine by agar dilutions because growth of the organism tended to diminish gradually over several dilutions. Six patients with disease due to rapidly growing mycobacteria were treated with sulfonamides, and all showed a good response to therapy. Sulfonamides may be the treatment of choice for infections due to M. fortuitum and offer potential for the therapy of disease due to M. chelonei.
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PMID:Sulfonamide activity against Mycobacterium fortuitum and Mycobacterium chelonei. 733 21

We report the successful treatment of disseminated Mycobacterium intracellulare osteomyelitis, without evidence of other visceral involvement, in a previously healthy, HIV-negative, 2-year-old female using a 23-month regimen of antimicrobial agents that included 18 months of oral therapy with azithromycin, rifabutin, trimethoprim-sulfamethoxazole (TMP/SMX), and ethambutol.
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PMID:Multifocal M. intracellulare osteomyelitis in an immunocompetent child. 781 41

Reports from the 1997 Fourth Conference on Retroviruses and Opportunistic Infections reveal encouraging responses to the latest antiretroviral regimens, including using protease inhibitors for treating opportunistic infections. Unfortunately, there appears to be less interest in the development and validation of newer agents and regimens for opportunistic infection treatment and prevention. Reports are presented addressing the following areas: the impact of opportunistic infections on survival in HIV-infected patients; the success of protease inhibitors and antiretroviral therapy on opportunistic infections; the relationship of viral load plus CD4+ levels and prophylactic therapy for opportunistic infections. A report indicating that patients with a history of previous febrile reactions to trimethoprim/sulfamethoxazole (TMP/SMX) may be at increased risk of recurrence of TMP/SMX hypersensitivity following initiation of protease inhibitor therapy, and studies suggesting that, in HIV-infected patients, cytomegalovirus reactivation occurs a median of six months prior to the development of clinically detectable manifestations of cytomegalovirus infection are included. Questions on the length of prophylactic therapy and the role of prophylaxis in anergic patients who are being treated for Mycobacterium disease; risk factors associated with recurrent oral candidiasis in patients who received continuous antifungal therapy for less than three months; the detection of human herpesvirus eight DNA sequences in the semen of HIV-infected men without Kaposi's sarcoma; and occurrences of cervical dysplasia and genital tract infections in HIV-infected women are also discussed.
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PMID:Opportunistic infections: stemming the tide. 1136 2

The X-ray structure of Mycobacterium tuberculosis TMP kinase at 1.95 A resolution is described as a binary complex with its natural substrate TMP. Its main features involve: (i) a clear magnesium-binding site; (ii) an alpha-helical conformation for the so-called LID region; and (iii) a high density of positive charges in the active site. There is a network of interactions involving highly conserved side-chains of the protein, the magnesium ion, a sulphate ion mimicking the beta phosphate group of ATP and the TMP molecule itself. All these interactions conspire in stabilizing what appears to be the closed form of the enzyme. A complete multialignment of all (32) known sequences of TMP kinases is presented. Subtle differences in the TMP binding site were noted, as compared to the Escherichia coli, yeast and human enzyme structures, which have been reported recently. These differences could be used to design specific inhibitors of this essential enzyme of nucleotide metabolism. Two cases of compensatory mutations were detected in the TMP binding site of eukaryotic and prokaryotic enzymes. In addition, an intriguing high value of the electric field is reported in the vicinity of the phosphate group of TMP and the putative binding site of the gamma phosphate group of ATP.
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PMID:X-ray structure of TMP kinase from Mycobacterium tuberculosis complexed with TMP at 1.95 A resolution. 1146 59

Caged compounds in combination with protein crystallography represent a valuable tool in studies of enzyme reaction intermediates. To date, photochemical triggering of reactions has been performed close to room temperature. Synchronous reaction initiation has only been achieved with enzymes of relatively slow turnover (<0.1 s(-1)) and caged compounds of high quantum yield. Here X-ray crystallography and microspectrophotometry were used to provide evidence that (nitrophenyl)ethyl (NPE) ester bonds can be photolyzed by UV light at cryotemperatures. NPE-caged ATP in flash-cooled crystals of Mycobacterium tuberculosis thymidylate kinase was photolyzed successfully at 100-150 K as assessed by the structural observation of ATP-dependent enzymatic conversion of TMP to TDP after temporarily warming the crystals to room temperature. A new method is proposed in which cryo-photolysis combined with temperature-controlled protein crystallography can be used to trap reaction intermediates even in some of the fastest enzymes and/or when only compounds of low quantum yield are available. Raising the temperature after cryophotolysis may allow a transition barrier to be passed and an intermediate to accumulate in the crystal. A comparable method has only been used so far with proteins displaying endogenous photosensitivity. The approach described here opens the way to studying the reaction mechanisms of a much larger number of crystalline enzymes. Furthermore, it is shown that X-ray-induced radiolysis of caged compounds occurs if high-intensity synchrotron beamlines are used. This caveat should be taken into account when deriving data-collection protocols. It could also be used potentially as a way to trigger reactions.
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PMID:Cryophotolysis of caged compounds: a technique for trapping intermediate states in protein crystals. 1191 84

African human immunodeficiency virus type 1 (HIV-1)-infected children were evaluated to define the burden of Pneumocystis carinii pneumonia (PCP) and its interaction with bacterial and viral pathogens. P. carinii was identified in 101 (43.7%) of 231 episodes of pneumonia among 185 HIV-1-infected children (median age, 4.5 months; range, 1.7-27.3 months). Receipt of trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis was not associated with a significant reduction (36%; 95% confidence interval [CI], -15.4% to 64.5%) in isolation of P. carinii among children considered to have received adequate prophylaxis (37.7% of children) compared with children who had never received any prophylaxis (48.5% of children). However, deaths among children with PCP who had been taking TMP-SMX prophylaxis were markedly reduced (98.6%; 95% CI, 89.1%-99.8%) compared with children who were not taking prophylaxis. Concurrent P. carinii infection was observed in 6 of 18, 11 of 26, and 4 of 6 HIV-1-infected children who had bacteremia, a respiratory virus isolated, or Mycobacterium species isolated, respectively.
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PMID:Ineffectiveness of trimethoprim-sulfamethoxazole prophylaxis and the importance of bacterial and viral coinfections in African children with Pneumocystis carinii pneumonia. 1295 58

The chemical synthesis of new compounds designed as inhibitors of Mycobacterium tuberculosis TMP kinase (TMPK) is reported. The synthesis concerns TMP analogues modified at the 5-position of the thymine ring as well as a novel compound with a six-membered sugar ring. The binding properties of the analogues are compared with the known inhibitor azido-TMP, which is postulated here to work by excluding the TMP-bound Mg(2+) ion. The crystallographic structure of the complex of one of the compounds, 5-CH(2)OH-dUMP, with TMPK has been determined at 2.0 A. It reveals a major conformation for the hydroxyl group in contact with a water molecule and a minor conformation pointing toward Ser(99). Looking for a role for Ser(99), we have identified an unusual catalytic triad, or a proton wire, made of strictly conserved residues (including Glu(6), Ser(99), Arg(95), and Asp(9)) that probably serves to protonate the transferred PO(3) group. The crystallographic structure of the commercially available bisubstrate analogue P(1)-(adenosine-5')-P(5)-(thymidine-5')-pentaphosphate bound to TMPK is also reported at 2.45 A and reveals an alternative binding pocket for the adenine moiety of the molecule compared with what is observed either in the Escherichia coli or in the yeast enzyme structures. This alternative binding pocket opens a way for the design of a new family of specific inhibitors.
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PMID:Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism. 1245 11

Mycobacterium tuberculosis TMP kinase (TMPK(Mtub)) represents a promising target for developing drugs against tuberculosis because the configuration of its active site is unique in the TMPK family. To help elucidate the phosphorylation mechanism employed by this enzyme, structural changes occurring upon binding of substrates and subsequent catalysis were investigated by protein crystallography. Six new structures of TMPK(Mtub) were solved at a resolution better than 2.3A, including the first structure of an apo-TMPK, obtained by triggering catalysis in a crystal of a TMPK(Mtub)-TMP complex, which resulted in the release of the TDP product. A series of snapshots along the reaction pathway is obtained, revealing the closure of the active site in going from an empty to a fully occupied state, suggestive of an induced-fit mechanism typical of NMPKs. However, in TMPK(Mtub) the LID closure couples to the binding with an unusual location for a magnesium ion coordinating TMP in the active site. Our data suggest strongly that this ion is required for catalysis, acting as a clamp, possibly in concert with Arg95, to neutralise electrostatic repulsion between the anionic substrates, optimise their proper alignment and activate them through direct and water-mediated interactions. The 3'-hydroxyl moiety of TMP, critical to metal stabilisation, appears to be a target of choice for the design of potent inhibitors. On the other hand, the usual NTP-bound magnesium is not seen in our structures and Arg14, a P-loop residue unique to TMPK(Mtub), may take over its role. Therefore, TMPK(Mtub) seems to have swapped the use of a metal ion as compared with e.g. human TMPK. Finally, TTP was observed in crystals of TMPK(Mtub), locked by Arg14, thus providing a structural explanation for the observed inhibitory effect of TTP putatively involved in a mechanism of feedback regulation of the enzymatic activity.
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PMID:Mycobacterium tuberculosis thymidylate kinase: structural studies of intermediates along the reaction pathway. 1266 32

Five cases of systemic Nocardia infection were diagnosed among 301 allogeneic bone marrow transplant recipients. A sixth case included in this report received her transplant at another institution. The cumulative annual incidence rate of this infection was 1.75%. All patients had been treated previously for acute graft-versus-host disease (GVHD). At the time of diagnosis of systemic Nocardia infection, a median of 198 (range 148-1121) days after transplantation, all patients had extensive chronic GVHD and were taking 2 to 3 immunosuppressive medications. Prior to diagnosis of Nocardia infection patients had experienced multiple opportunistic infections, including infections with Mycobacterium avium-intracellulare, Pneumocystis carinii, and cytomegalovirus antigenemia. Treatment with trimethoprim-sulfamethoxazole (TMP-SMX), ceftriaxone, or carbapenem antibiotics resulted in a median survival of 219 days from the time of diagnosis and an actuarial 1-year survival of 40%. All patients who received more than 2 weeks of therapy were cured of their infections. Notably, 5/6 patients in this cohort were unable to take TMP-SMX because of myelosuppression. In comparison with randomly selected control patients, the use of pentamidine for prevention of P. carinii infection was associated with a marginal increase in the risk of Nocardia infection. We postulate that the use of TMP-SMX may be of benefit in the prophylaxis of infections other than P. carinii in patients with chronic GVHD.
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PMID:Systemic nocardiosis following allogeneic bone marrow transplantation. 1279 Oct 70


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