Base de dados : MEDLINE
Pesquisa : D03.066.349.220 [Categoria DeCS]
Referências encontradas : 939 [refinar]
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[PMID]:28591540
[Au] Autor:Rubin EJ
[Ad] Endereço:From the Department of Immunology and Infectious Diseases, the Harvard T.H. Chan School of Public Health, Boston.
[Ti] Título:Reviving a Drug for Tuberculosis?
[So] Source:N Engl J Med;376(23):2292-2294, 2017 Jun 08.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Antibióticos Antituberculose/uso terapêutico
Etionamida/uso terapêutico
Isoxazóis/uso terapêutico
Mycobacterium tuberculosis/metabolismo
Pró-Fármacos/uso terapêutico
Proteínas Repressoras/antagonistas & inibidores
Compostos de Espiro/uso terapêutico
Tuberculose/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Antibióticos Antituberculose/metabolismo
Farmacorresistência Bacteriana
Etionamida/metabolismo
Seres Humanos
Isoxazóis/metabolismo
Camundongos
Oxirredutases/metabolismo
Pró-Fármacos/metabolismo
Proteínas Repressoras/metabolismo
Compostos de Espiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antitubercular); 0 (EthR protein, Mycobacterium tuberculosis); 0 (Isoxazoles); 0 (Prodrugs); 0 (Repressor Proteins); 0 (SMARt-420); 0 (Spiro Compounds); EC 1.- (Oxidoreductases); EC 1.3.1.9 (ethA protein, Mycobacterium tuberculosis); OAY8ORS3CQ (Ethionamide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMcibr1703502


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[PMID]:28314097
[Au] Autor:Nikiforov PO; Blaszczyk M; Surade S; Boshoff HI; Sajid A; Delorme V; Deboosere N; Brodin P; Baulard AR; Barry CE; Blundell TL; Abell C
[Ad] Endereço:Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
[Ti] Título:Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays.
[So] Source:ACS Chem Biol;12(5):1390-1396, 2017 May 19.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Small-molecule inhibitors of the mycobacterial transcriptional repressor EthR have previously been shown to act as boosters of the second-line antituberculosis drug ethionamide. Fragment-based drug discovery approaches have been used in the past to make highly potent EthR inhibitors with ethionamide boosting activity both in vitro and ex vivo. Herein, we report the development of fragment-sized EthR ligands with nanomolar minimum effective concentration values for boosting the ethionamide activity in Mycobacterium tuberculosis whole-cell assays.
[Mh] Termos MeSH primário: Etionamida/farmacologia
Mycobacterium tuberculosis/enzimologia
Proteínas Repressoras/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antituberculosos
Proteínas de Bactérias
Descoberta de Drogas
Sinergismo Farmacológico
Inibidores Enzimáticos/farmacologia
Inibidores Enzimáticos/uso terapêutico
Etionamida/uso terapêutico
Ligantes
Testes de Sensibilidade Microbiana
Mycobacterium tuberculosis/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Bacterial Proteins); 0 (Enzyme Inhibitors); 0 (EthR protein, Mycobacterium tuberculosis); 0 (Ligands); 0 (Repressor Proteins); OAY8ORS3CQ (Ethionamide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00091


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[PMID]:28302858
[Au] Autor:Blondiaux N; Moune M; Desroses M; Frita R; Flipo M; Mathys V; Soetaert K; Kiass M; Delorme V; Djaout K; Trebosc V; Kemmer C; Wintjens R; Wohlkönig A; Antoine R; Huot L; Hot D; Coscolla M; Feldmann J; Gagneux S; Locht C; Brodin P; Gitzinger M; Déprez B; Willand N; Baulard AR
[Ad] Endereço:Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
[Ti] Título:Reversion of antibiotic resistance in by spiroisoxazoline SMARt-420.
[So] Source:Science;355(6330):1206-1211, 2017 03 17.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in , circumventing the classic activation pathway in which resistance mutations have now been observed. The first-of-its-kind molecule, named SMARt-420 (Small Molecule Aborting Resistance), not only fully reverses ethionamide-acquired resistance and clears ethionamide-resistant infection in mice, it also increases the basal sensitivity of bacteria to ethionamide.
[Mh] Termos MeSH primário: Antituberculosos/farmacologia
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos
Etionamida/metabolismo
Tuberculose Extensivamente Resistente a Medicamentos/microbiologia
Isoxazóis/farmacologia
Mycobacterium tuberculosis/efeitos dos fármacos
Compostos de Espiro/farmacologia
[Mh] Termos MeSH secundário: Animais
DNA/metabolismo
Etionamida/farmacologia
Seres Humanos
Camundongos
Mutação
Mycobacterium tuberculosis/genética
Mycobacterium tuberculosis/metabolismo
Oxidiazóis/farmacologia
Piperidinas/farmacologia
Ligação Proteica/efeitos dos fármacos
Proteínas Repressoras/antagonistas & inibidores
Proteínas Repressoras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (5,5,5-trifluoro-1-(4-(3-thiazol-2-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pentan-1-one); 0 (Antitubercular Agents); 0 (EthR protein, Mycobacterium tuberculosis); 0 (Isoxazoles); 0 (Oxadiazoles); 0 (Piperidines); 0 (Repressor Proteins); 0 (SMARt-420); 0 (Spiro Compounds); 9007-49-2 (DNA); OAY8ORS3CQ (Ethionamide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE
[do] DOI:10.1126/science.aag1006


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[PMID]:28057421
[Au] Autor:Vale N; Correia A; Silva S; Figueiredo P; Mäkilä E; Salonen J; Hirvonen J; Pedrosa J; Santos HA; Fraga A
[Ad] Endereço:UCIBIO/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal. Electronic address: nuno.vale@fc.up.pt.
[Ti] Título:Preparation and biological evaluation of ethionamide-mesoporous silicon nanoparticles against Mycobacterium tuberculosis.
[So] Source:Bioorg Med Chem Lett;27(3):403-405, 2017 02 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Ethionamide (ETH) is an important second-line antituberculosis drug used for the treatment of patients infected with multidrug-resistant Mycobacterium tuberculosis. Recently, we reported that the loading of ETH into thermally carbonized-porous silicon (TCPSi) nanoparticles enhanced the solubility and permeability of ETH at different pH-values and also increased its metabolization process. Based on these results, we synthesized carboxylic acid functionalized thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) conjugated with ETH and its antimicrobial effect was evaluated against Mycobacterium tuberculosis strain H37Rv. The activity of the conjugate was increased when compared to free-ETH, which suggests that the nature of the synergy between the NPs and ETH is likely due to the weakening of the bacterial cell wall that improves conjugate-penetration. These ETH-conjugated NPs have great potential in reducing dosing frequency of ETH in the treatment of multidrug-resistant tuberculosis (MDR-TB).
[Mh] Termos MeSH primário: Antituberculosos/química
Etionamida/química
Nanopartículas/química
Silício/química
[Mh] Termos MeSH secundário: Antituberculosos/farmacologia
Antituberculosos/uso terapêutico
Etionamida/farmacologia
Etionamida/uso terapêutico
Seres Humanos
Testes de Sensibilidade Microbiana
Mycobacterium tuberculosis/efeitos dos fármacos
Tamanho da Partícula
Porosidade
Solubilidade
Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antitubercular Agents); OAY8ORS3CQ (Ethionamide); Z4152N8IUI (Silicon)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE


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[PMID]:27815138
[Au] Autor:Nechipadappu SK; R Trivedi D
[Ad] Endereço:Supramolecular Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka (NITK)-Surathkal, Srinivasnagar 575 025, Karnataka, India.
[Ti] Título:Pharmaceutical salts of ethionamide with GRAS counter ion donors to enhance the solubility.
[So] Source:Eur J Pharm Sci;96:578-589, 2017 Jan 01.
[Is] ISSN:1879-0720
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Pharmaceutical salts of BCS class II second line anti-tuberculosis drug ethionamide (ETH) with various counter ions namely, 2-chloro-4-nitrobenzoic acid (CNB), 2,6-dihydroxybenzoic acid (2,6HBA), 2,3-dihydroxybenzoic acid (2,3HBA) and 2,4-dinitrobenzoic acid (DNB) were synthesized by crystal engineering approach. All the synthesized salts were characterized by various spectroscopic (NMR, FT-IR,), thermal (DSC & TGA) and PXRD techniques. The crystal structure of the synthesized salts was determined by single-crystal X-ray diffraction techniques. All the reported salts, except ETH-2,3HBA exhibited charge assisted acid pyridine heterosynthon. In ETH-2,3HBA hydoxyl pyridine heterosynthon is observed. In ETH-CNB salt, both ionic and neutral acid pyridine heterosynthon were observed in the asymmetric unit. ETH-DNB salt consists of both partial and complete proton transfer from DNB to ETH in the asymmetric unit. All the synthesized salts were found to be non-hygroscopic at accelerated humid condition (~75% RH). Solubility experiment has been performed in purified water and in 0.1N HCl (pH=1) solution and found that the solubility of ETH-CNB salt was about eight-fold higher soluble than ETH in purified water. The solubility of synthesized salts follows the order of ETH
[Mh] Termos MeSH primário: Antituberculosos/análise
Antituberculosos/química
Etionamida/análise
Etionamida/química
[Mh] Termos MeSH secundário: Química Farmacêutica
Íons
Sais
Solubilidade
Espectroscopia de Infravermelho com Transformada de Fourier/métodos
Difração de Raios X/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Ions); 0 (Salts); OAY8ORS3CQ (Ethionamide)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170904
[Lr] Data última revisão:
170904
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161106
[St] Status:MEDLINE


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[PMID]:27524534
[Au] Autor:Akhtar AM; Arif MA; Kanwal S; Majeed S
[Ad] Endereço:Provincial TB Control Program, Punjab, DGHS, Lahore, Pakistan.
[Ti] Título:Prevalence and drug resistance pattern of MDR TB in retreatment cases of Punjab, Pakistan.
[So] Source:J Pak Med Assoc;66(8):989-93, 2016 Aug.
[Is] ISSN:0030-9982
[Cp] País de publicação:Pakistan
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To determine the prevalence and resistance pattern of multidrug-resistant tuberculosis. METHODS: This cross-sectional study was carried out from January 2010 to June 2014 in nine tertiary care hospitals implementing programmatic management of drug-resistant tuberculosis in Punjab, and comprised retreatment tuberculosis cases. Data was collected from the Electronic Nominal Review System. SPSS 17 was used for data analysis. RESULTS: Of the 1,250 cases, 861(69%) were of multidrug-resistant tuberculosis confirmed through drug sensitivity testing. The mean age was 32 (±13.5 SD) years. Besides, 664(53%) were males and 1,208(97%) resided in urban areas of Punjab. Multidrug-resistant tuberculosis was found to be more prevalent in the most productive age group, i.e. 15-45 years, with 709(57%) cases (p<0.05), in urban areas1, 208(97%) cases (p<0.05) and in the pulmonary site 852(68%) cases (p<0.05). Overall, 391(41%) cases showed resistance to all first-line anti-tuberculosis drugs while 239(28%) showed resistance to oral first-line drugs. Besides, 526(42%) cases showed resistance to fluoroquinolones and 650(52%) to second-line drugs. Of them, 420(81%), (p<0.05) patients showed highly significant resistance to fluoroquinolones and 26(5%) to ethionamide. CONCLUSIONS: There is a need to fully implement national tuberculosis guidelines with a focus on expansion and effective implementation of directly observed therapy short course in order to prevent further emergence of drug resistance.
[Mh] Termos MeSH primário: Farmacorresistência Bacteriana Múltipla
Mycobacterium tuberculosis/fisiologia
Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Antituberculosos/uso terapêutico
Criança
Pré-Escolar
Estudos Transversais
Etionamida
Feminino
Fluoroquinolonas
Seres Humanos
Lactente
Recém-Nascido
Masculino
Testes de Sensibilidade Microbiana
Meia-Idade
Paquistão/epidemiologia
Prevalência
Retratamento
Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Fluoroquinolones); OAY8ORS3CQ (Ethionamide)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170113
[Lr] Data última revisão:
170113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160816
[St] Status:MEDLINE


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[PMID]:27451820
[Au] Autor:Prasad R; Singh A; Srivastava R; Hosmane GB; Kushwaha RA; Jain A
[Ad] Endereço:Department of Pulmonary Medicine, King George Medical University, Lucknow, India. Electronic address: rprasadkgmc@gmail.com.
[Ti] Título:Frequency of adverse events observed with second-line drugs among patients treated for multidrug-resistant tuberculosis.
[So] Source:Indian J Tuberc;63(2):106-14, 2016 04.
[Is] ISSN:0019-5707
[Cp] País de publicação:India
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is considered to be a worldwide problem with notoriously difficult and challenging treatment. Adverse events associated with second-line drugs (SLDs) can have severe impact on efficient management. OBJECTIVE: To know the frequency of adverse events due to SLDs in patients of MDR-TB. DESIGN: A prospective cohort analysis of 98 MDR-TB patients enrolled between June 2009 to February 2010 was conducted in Department of Pulmonary Medicine, King George Medical University, Lucknow, India. All the patients were provided standardized regimen. Adverse events associated with treatment were recognized primarily by clinical evidence and/or laboratory investigations that were advised at baseline and whenever clinically indicated during course of treatment. Adverse events were considered major if required permanent discontinuation or substitution of drugs. RESULTS: 119 adverse events were reported in 46 (46.9%) patients. The grouped adverse events were most commonly gastrointestinal that was observed with a frequency of 48 (40.3%) followed by ototoxicity in 28 (23.6%), and neurological in 21 (17.6%). 17 (17.4%) patients had major adverse events requiring permanent discontinuation or substitution of drugs that included deafness and tinnitus in 5 (5.1%) followed by psychosis in 4 (4.1%). None of the patients stopped complete regimen due to adverse events. The treatment success rate was observed to be 71 (72.4%). CONCLUSIONS: MDR-TB can be cured successfully with appropriate combination of drugs if adverse events associated with them can be managed aggressively and timely. Newer and less toxic drugs are urgently needed to treat MDR-TB patients.
[Mh] Termos MeSH primário: Antituberculosos/efeitos adversos
Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Estudos de Coortes
Ciclosserina/efeitos adversos
Quimioterapia Combinada
Etambutol/efeitos adversos
Etionamida/efeitos adversos
Feminino
Seres Humanos
Canamicina/efeitos adversos
Masculino
Ofloxacino/efeitos adversos
Pirazinamida/efeitos adversos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 2KNI5N06TI (Pyrazinamide); 59-01-8 (Kanamycin); 8G167061QZ (Ethambutol); 95IK5KI84Z (Cycloserine); A4P49JAZ9H (Ofloxacin); OAY8ORS3CQ (Ethionamide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160726
[St] Status:MEDLINE


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[PMID]:27344049
[Au] Autor:Catucci G; Zgrablic I; Lanciani F; Valetti F; Minerdi D; Ballou DP; Gilardi G; Sadeghi SJ
[Ad] Endereço:Department of Life Sciences and Systems Biology, University of Torino, 10123 Turin, Italy.
[Ti] Título:Characterization of a new Baeyer-Villiger monooxygenase and conversion to a solely N-or S-oxidizing enzyme by a single R292 mutation.
[So] Source:Biochim Biophys Acta;1864(9):1177-1187, 2016 09.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Ar-BVMO is a recently discovered Baeyer-Villiger monooxygenase from the genome of Acinetobacter radioresistens S13 closely related to medically relevant ethionamide monooxygenase EtaA (prodrug activator) and capable of inactivating the imipenem antibiotic. METHODS: The co-substrate preference as well as steady-state and rapid kinetics studies of the recombinant purified protein were carried out using stopped-flow spectroscopy under anaerobic and aerobic conditions. Kd values were measured by isothermal calorimetry. Enzymatic activity was determined by measuring the amount of product formed using high pressure liquid chromatography or gas chromatography. Site-directed mutagenesis experiments were performed to decipher the role of the active site arginine-292. RESULTS: Ar-BVMO was found to oxidize ethionamide as well as linear ketones. Mechanistic studies on the wild type enzyme using stopped-flow spectroscopy allowed for the detection of the characteristic oxygenating C4a-(hydro)peroxyflavin intermediate, which decayed rapidly in the presence of the substrate. Replacement of arginine 292 in Ar-BVMO by glycine or alanine resulted in greatly reduced or no Baeyer-Villiger activity, respectively, demonstrating the crucial role of this residue in catalysis of ketone substrates. However, both the R292A and R292G mutants are capable of carrying out N- and S-oxidation reactions. CONCLUSIONS: Substrate profiling of Ar-BVMO confirms its close relationship to EtaA; ethionamide is one of its substrates. The active site Arginine 292 is required for its Baeyer-Villiger activity but not for heteroatom oxidation. GENERAL SIGNIFICANCE: A single mutation converts Ar-BVMO to a unique S- or N-monooxygenase, a useful biocatalyst for the production of oxidized metabolites of human drug metabolizing enzymes.
[Mh] Termos MeSH primário: Acinetobacter/enzimologia
Proteínas de Bactérias/química
Etionamida/química
Flavinas/química
Cetonas/química
Oxigenases de Função Mista/química
Microbiologia do Solo
[Mh] Termos MeSH secundário: Acinetobacter/genética
Alanina/química
Alanina/metabolismo
Sequência de Aminoácidos
Arginina/química
Arginina/metabolismo
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Biocatálise
Domínio Catalítico
Clonagem Molecular
Escherichia coli/genética
Escherichia coli/metabolismo
Etionamida/metabolismo
Flavinas/metabolismo
Expressão Gênica
Glicina/química
Glicina/metabolismo
Cetonas/metabolismo
Cinética
Oxigenases de Função Mista/genética
Oxigenases de Função Mista/metabolismo
Mutagênese Sítio-Dirigida
Mutação
Oxirredução
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (C4a-hydroperoxyflavin); 0 (Flavins); 0 (Ketones); 0 (Recombinant Proteins); 94ZLA3W45F (Arginine); EC 1.- (Mixed Function Oxygenases); OAY8ORS3CQ (Ethionamide); OF5P57N2ZX (Alanine); TE7660XO1C (Glycine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160626
[St] Status:MEDLINE


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[PMID]:27321573
[Au] Autor:Grant SS; Wellington S; Kawate T; Desjardins CA; Silvis MR; Wivagg C; Thompson M; Gordon K; Kazyanskaya E; Nietupski R; Haseley N; Iwase N; Earl AM; Fitzgerald M; Hung DT
[Ad] Endereço:Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Center for Computational and Integrative Biology, Massachusetts General Hospit
[Ti] Título:Baeyer-Villiger Monooxygenases EthA and MymA Are Required for Activation of Replicating and Non-replicating Mycobacterium tuberculosis Inhibitors.
[So] Source:Cell Chem Biol;23(6):666-77, 2016 Jun 23.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Successful treatment of Mycobacterium tuberculosis infection typically requires a complex regimen administered over at least 6 months. Interestingly, many of the antibiotics used to treat M. tuberculosis are prodrugs that require intracellular activation. Here, we describe three small molecules, active against both replicating and non-replicating M. tuberculosis, that require activation by Baeyer-Villiger monooxygenases (BVMOs). Two molecules require BVMO EthA (Rv3854c) for activation and the third molecule requires the BVMO MymA (Rv3083). While EthA is known to activate the antitubercular drug ethionamide, this is the first description of MymA as an activating enzyme of a prodrug. Furthermore, we found that MymA also plays a role in activating ethionamide, with loss of MymA function resulting in ethionamide-resistant M. tuberculosis. These findings suggest overlap in function and specificity of the BVMOs in M. tuberculosis.
[Mh] Termos MeSH primário: Antituberculosos/farmacologia
Etionamida/farmacologia
Oxigenases de Função Mista/metabolismo
Mycobacterium tuberculosis/efeitos dos fármacos
Mycobacterium tuberculosis/crescimento & desenvolvimento
Oxirredutases/metabolismo
Bibliotecas de Moléculas Pequenas/farmacologia
[Mh] Termos MeSH secundário: Antituberculosos/química
Relação Dose-Resposta a Droga
Farmacorresistência Bacteriana/efeitos dos fármacos
Etionamida/química
Oxigenases de Função Mista/genética
Estrutura Molecular
Mycobacterium tuberculosis/enzimologia
Mycobacterium tuberculosis/metabolismo
Oxirredutases/genética
Bibliotecas de Moléculas Pequenas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Small Molecule Libraries); EC 1.- (Mixed Function Oxygenases); EC 1.- (Oxidoreductases); EC 1.3.1.9 (ethA protein, Mycobacterium tuberculosis); OAY8ORS3CQ (Ethionamide)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160621
[St] Status:MEDLINE


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[PMID]:26806381
[Au] Autor:Nikiforov PO; Surade S; Blaszczyk M; Delorme V; Brodin P; Baulard AR; Blundell TL; Abell C
[Ad] Endereço:Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. ca26@cam.ac.uk.
[Ti] Título:A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.
[So] Source:Org Biomol Chem;14(7):2318-26, 2016 Feb 21.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.
[Mh] Termos MeSH primário: Etionamida/química
Mycobacterium tuberculosis/efeitos dos fármacos
Proteínas Repressoras/efeitos dos fármacos
Bibliotecas de Moléculas Pequenas/química
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Etionamida/farmacologia
Interações Hidrofóbicas e Hidrofílicas
Concentração Inibidora 50
Estrutura Molecular
Bibliotecas de Moléculas Pequenas/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (EthR protein, Mycobacterium tuberculosis); 0 (Repressor Proteins); 0 (Small Molecule Libraries); OAY8ORS3CQ (Ethionamide)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160126
[St] Status:MEDLINE
[do] DOI:10.1039/c5ob02630j



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