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[PMID]:27776597
[Au] Autor:Pina RZ; Caleffi-Ferracioli KR; Campanerut-Sá PA; Ghiraldi-Lopez LD; Pavan FR; Siqueira VL; Scodro RB; Cardoso RF
[Ad] Endereço:Post-Graduate Programme in Health Sciences, State University of Maringá, Maringá, Brazil.
[Ti] Título:Pyrazinamide susceptibility testing in Mycobacterium tuberculosis using the fast resazurin microtiter assay plate.
[So] Source:Int J Tuberc Lung Dis;20(11):1535-1538, 2016 Nov.
[Is] ISSN:1815-7920
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:SETTING: Department of Clinical Analysis and Biomedicine, State University of Maringa, Maringa, PR, Brazil. OBJECTIVE: To evaluate the performance of the resazurin microtiter assay (REMA) plate at pH 5.5 in detecting Mycobacterium tuberculosis susceptibility to pyrazinamide (PZA). DESIGN: The minimal inhibitory concentration (MIC) of PZA in M. tuberculosis H Rv and M. bovis AN5 reference strains and in 34 clinical M. tuberculosis isolates (26 PZA-susceptible and eight PZA-resistant) was determined using REMA at pH 5.5 and compared to REMA at pH 6.0. RESULTS: REMA at pH 5.5 was helpful in discriminating PZA-susceptible from resistant M. tuberculosis isolates when â©¿50 µg/ml PZA was considered as the cut-off for PZA susceptibility. Furthermore, it provided results in 8 days. However, two PZA-resistant isolates failed to grow at pH 5.5. CONCLUSION: As the REMA method is rapid, inexpensive, easy to perform and read, it would be of great usefulness in low-income countries for detecting PZA-resistant M. tuberculosis. REMA at pH 5.6-5.9 should be evaluated on an extended panel of clinical M. tuberculosis isolates with a greater range of MIC values in different laboratories for a better understanding of its utility in differentiating PZA-resistant from PZA-susceptible isolates.
[Mh] Termos MeSH primário: Antituberculosos/farmacologia
Farmacorresistência Bacteriana
Testes de Sensibilidade Microbiana/métodos
Mycobacterium tuberculosis/efeitos dos fármacos
Pirazinamida/farmacologia
[Mh] Termos MeSH secundário: Brasil
Seres Humanos
Concentração de Íons de Hidrogênio
Oxazinas
Xantenos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Oxazines); 0 (Xanthenes); 1FN9YD6968 (resazurin); 2KNI5N06TI (Pyrazinamide)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


  2 / 2666 MEDLINE  
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[PMID]:29088294
[Au] Autor:Ngabonziza JCS; Diallo AB; Tagliani E; Diarra B; Kadanga AE; Togo ACG; Thiam A; de Rijk WB; Alagna R; Houeto S; Ba F; Dagnra AY; Ivan E; Affolabi D; Schwoebel V; Trebucq A; de Jong BC; Rigouts L; Daneau G; "Union short MDR-TB regimen study group"
[Ad] Endereço:National Reference Laboratory Division, Biomedical Services Department, Rwanda Biomedical Centre, Kigali, Rwanda.
[Ti] Título:Half of rifampicin-resistant Mycobacterium tuberculosis complex isolated from tuberculosis patients in Sub-Saharan Africa have concomitant resistance to pyrazinamide.
[So] Source:PLoS One;12(10):e0187211, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Besides inclusion in 1st line regimens against tuberculosis (TB), pyrazinamide (PZA) is used in 2nd line anti-TB regimens, including in the short regimen for multidrug-resistant TB (MDR-TB) patients. Guidelines and expert opinions are contradictory about inclusion of PZA in case of resistance. Moreover, drug susceptibility testing (DST) for PZA is not often applied in routine testing, and the prevalence of resistance is unknown in several regions, including in most African countries. METHODS: Six hundred and twenty-three culture isolates from rifampicin-resistant (RR) patients were collected in twelve Sub-Saharan African countries. Among those isolates, 71% were from patients included in the study on the Union short-course regimen for MDR-TB in Benin, Burkina Faso, Burundi, Cameroon, Central Africa Republic, the Democratic Republic of the Congo, Ivory Coast, Niger, and Rwanda PZA resistance, and the rest (29%) were consecutive isolates systematically stored from 2014-2015 in Mali, Rwanda, Senegal, and Togo. Besides national guidelines, the isolates were tested for PZA resistance through pncA gene sequencing. RESULTS: Over half of these RR-TB isolates (54%) showed a mutation in the pncA gene, with a significant heterogeneity between countries. Isolates with fluoroquinolone resistance (but not with injectable resistance or XDR) were more likely to have concurrent PZA resistance. The pattern of mutations in the pncA gene was quite diverse, although some isolates with an identical pattern of mutations in pncA and other drug-related genes were isolated from the same reference center, suggesting possible transmission of these strains. CONCLUSION: Similar to findings in other regions, more than half of the patients having RR-TB in West and Central Africa present concomitant resistance to PZA. Further investigations are needed to understand the relation between resistance to PZA and resistance to fluoroquinolones, and whether continued use of PZA in the face of PZA resistance provides clinical benefit to the patients.
[Mh] Termos MeSH primário: Antituberculosos/uso terapêutico
Mycobacterium tuberculosis/efeitos dos fármacos
Pirazinamida/uso terapêutico
Rifampina/uso terapêutico
Tuberculose Pulmonar/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Adulto
África ao Sul do Saara/epidemiologia
Idoso
Idoso de 80 Anos ou mais
Amidoidrolases/genética
Criança
Farmacorresistência Bacteriana Múltipla/genética
Feminino
Seres Humanos
Masculino
Meia-Idade
Mycobacterium tuberculosis/genética
Tuberculose Pulmonar/microbiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 2KNI5N06TI (Pyrazinamide); EC 3.5.- (Amidohydrolases); EC 3.5.- (PncA protein, Mycobacterium tuberculosis); VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171101
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0187211


  3 / 2666 MEDLINE  
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[PMID]:28870094
[Au] Autor:Zhou S; Yang S; Huang G
[Ad] Endereço:a College of Chemistry , Chongqing Normal University , Chongqing , China.
[Ti] Título:Design, synthesis and biological activity of pyrazinamide derivatives for anti-Mycobacterium tuberculosis.
[So] Source:J Enzyme Inhib Med Chem;32(1):1183-1186, 2017 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A total of 11 pyrazinamide derivatives were designed and synthesised using pyrazinamide as the lead compound, which was optimised by structural modification with alkyl chains, six-membered rings, and bioisosterism, respectively. The target compounds were synthesised using pyrazinecarboxylic acid as the starting material by acylation, amidation, and alkylation, respectively. Their structures were confirmed by H NMR, C NMR, HRESIMS, and elemental analysis, respectively. The bioactivities of derivatives were assayed using bacteriostatic experiment and minimum inhibitory concentration experiment. It was showed that the derivatives had good inhibitory effect on Mycobacterium tuberculosis. The biological activity of derivative 1f was the best among all compounds, its antibacterial activity was 99.6%, and the minimum inhibitory concentration was 8.0 µg/mL.
[Mh] Termos MeSH primário: Antituberculosos/farmacologia
Desenho de Drogas
Mycobacterium tuberculosis/efeitos dos fármacos
Pirazinamida/farmacologia
[Mh] Termos MeSH secundário: Antituberculosos/síntese química
Antituberculosos/química
Relação Dose-Resposta a Droga
Testes de Sensibilidade Microbiana
Estrutura Molecular
Pirazinamida/síntese química
Pirazinamida/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 2KNI5N06TI (Pyrazinamide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1367774


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[PMID]:28761946
[Au] Autor:Zenner D; Beer N; Harris RJ; Lipman MC; Stagg HR; van der Werf MJ
[Ad] Endereço:From Institute for Global Health, University College London; Public Health England; and Royal Free London National Health Service Foundation Trust, London, United Kingdom, and European Centre for Disease Prevention and Control, Stockholm, Sweden.
[Ti] Título:Treatment of Latent Tuberculosis Infection: An Updated Network Meta-analysis.
[So] Source:Ann Intern Med;167(4):248-255, 2017 Aug 15.
[Is] ISSN:1539-3704
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI. Purpose: To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children. Data Sources: PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied. Study Selection: Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB). Data Extraction: 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol. Data Synthesis: The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy. Limitation: Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies. Conclusion: Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin. Primary Funding Source: U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).
[Mh] Termos MeSH primário: Antituberculosos/uso terapêutico
Isoniazida/uso terapêutico
Tuberculose Latente/tratamento farmacológico
Pirazinamida/uso terapêutico
Rifampina/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Antituberculosos/efeitos adversos
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Criança
Combinação de Medicamentos
Seres Humanos
Isoniazida/efeitos adversos
Metanálise em Rede
Pirazinamida/efeitos adversos
Rifampina/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Drug Combinations); 0 (isoniazid, pyrazinamide, rifampin drug combination); 2KNI5N06TI (Pyrazinamide); V83O1VOZ8L (Isoniazid); VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE
[do] DOI:10.7326/M17-0609


  5 / 2666 MEDLINE  
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[PMID]:28697808
[Au] Autor:Sengstake S; Bergval IL; Schuitema AR; de Beer JL; Phelan J; de Zwaan R; Clark TG; van Soolingen D; Anthony RM
[Ad] Endereço:Royal Tropical Institute, KIT Biomedical Research, Meibergdreef 39, 1105 AZ, Amsterdam, The Netherlands. sarah.sengstake@gmail.com.
[Ti] Título:Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia.
[So] Source:BMC Infect Dis;17(1):491, 2017 Jul 12.
[Is] ISSN:1471-2334
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The ongoing epidemic of multidrug-resistant tuberculosis (MDR-TB) in Georgia highlights the need for more effective control strategies. A new regimen to treat MDR-TB that includes pyrazinamide (PZA) is currently being evaluated and PZA resistance status will largely influence the success of current and future treatment strategies. PZA susceptibility testing was not routinely performed at the National Reference Laboratory (NRL) in Tbilisi between 2010 and September 2015. We here provide a first insight into the prevalence of PZA resistant TB in this region. METHODS: Phenotypic susceptibility to PZA was determined in a convenience collection of well-characterised TB patient isolates collected at the NRL in Tbilisi between 2012 and 2013. In addition, the pncA gene was sequenced and whole genome sequencing was performed on two isolates. RESULTS: Out of 57 isolates tested 33 (57.9%) showed phenotypic drug resistance to PZA and had a single pncA mutation. All of these 33 isolates were MDR-TB strains. pncA mutations were absent in all but one of the 24 PZA susceptible isolate. In total we found 18 polymorphisms in the pncA gene. From the two major MDR-TB clusters represented (94-32 and 100-32), 10 of 15, 67.0% and 13 of 14, 93.0% strains, respectively were PZA resistant. We also identified a member of the potentially highly transmissive clade A strain carrying the characteristic I6L substitution in PncA. Another strain with the same MLVA type as the clade A strain acquired a different mutation in pncA and was genetically more distantly related suggesting that different branches of this particular lineage have been introduced into this region. CONCLUSION: In this high MDR-TB setting more than half of the tested MDR-TB isolates were resistant to PZA. As PZA is part of current and planned MDR-TB treatment regimens this is alarming and deserves the attention of health authorities. Based on our typing and sequence analysis results we conclude that PZA resistance is the result of primary transmission as well as acquisition within the patient and recommend prospective genotyping and PZA resistance testing in high MDR-TB settings. This is of utmost importance in order to preserve bacterial susceptibility to PZA to help protect (new) second line drugs in PZA containing regimens.
[Mh] Termos MeSH primário: Amidoidrolases/genética
Mutação
Mycobacterium tuberculosis/efeitos dos fármacos
Pirazinamida/farmacologia
Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
[Mh] Termos MeSH secundário: Antituberculosos/farmacologia
Antituberculosos/uso terapêutico
Genótipo
República da Geórgia/epidemiologia
Seres Humanos
Testes de Sensibilidade Microbiana
Mycobacterium tuberculosis/genética
Mycobacterium tuberculosis/isolamento & purificação
Prevalência
Estudos Prospectivos
Pirazinamida/uso terapêutico
Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
Tuberculose Resistente a Múltiplos Medicamentos/transmissão
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 2KNI5N06TI (Pyrazinamide); EC 3.5.- (Amidohydrolases); EC 3.5.- (PncA protein, Mycobacterium tuberculosis)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1186/s12879-017-2594-3


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[PMID]:28653928
[Au] Autor:Ali M; Qader SA; Shahid F; Arayne MS; Mumtaz M
[Ad] Endereço:Department of Chemistry, University of Karachi, Karachi, Pakistan.
[Ti] Título:Synthesis, characterization and enzyme inhibitory activity of new pyrazinamide iron complexes.
[So] Source:Pak J Pharm Sci;30(3):825-831, 2017 May.
[Is] ISSN:1011-601X
[Cp] País de publicação:Pakistan
[La] Idioma:eng
[Ab] Resumo:The present paper deals with synthesis, characterization and amylase inhibitory activity of pyrazinamide (PYZ) with iron in its both (II) and (III) oxidation states. The synthesized complexes were characterized on the basis of IR, UV, H-NMR, C-NMR, elemental analysis and SEM. Changes in IR data shows that PYZ form complex with octahedral geometry and binding sites are ring nitrogen and carbonyl group, wherein two sides are satisfied with two chloride ions. SEM images indicate the crystalline state and surface morphology of PYZ and its complexes. Elemental analysis proves the composition of complexes. Pyrazinamide and the complexes showed no significant effect on amylase activity but the activity was inhibited in the presence of ferrous chloride.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Ferro/química
Pirazinamida/química
[Mh] Termos MeSH secundário: Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Microscopia Eletrônica de Varredura
Análise Espectral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 2KNI5N06TI (Pyrazinamide); E1UOL152H7 (Iron)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE


  7 / 2666 MEDLINE  
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[PMID]:28538778
[Au] Autor:Silva VDD; Mello FCQ; Figueiredo SCA
[Ad] Endereço:. Programa de Pós-Graduação, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil.
[Ti] Título:Estimated rates of recurrence, cure, and treatment abandonment in patients with pulmonary tuberculosis treated with a -four-drug fixed-dose combination regimen at a tertiary health care facility in the city of Rio de Janeiro, Brazil.
[So] Source:J Bras Pneumol;43(2):113-120, 2017 Mar-Apr.
[Is] ISSN:1806-3756
[Cp] País de publicação:Brazil
[La] Idioma:eng; por
[Ab] Resumo:Objective:: To estimate the rates of recurrence, cure, and treatment abandonment in patients with pulmonary tuberculosis treated with a four-drug fixed-dose combination (FDC) regimen, as well as to evaluate possible associated factors. Methods:: This was a retrospective observational study involving 208 patients with a confirmed diagnosis of pulmonary tuberculosis enrolled in the Hospital Tuberculosis Control Program at the Institute for Thoracic Diseases, located in the city of Rio de Janeiro, Brazil. Between January of 2007 and October of 2010, the patients were treated with the rifampin-isoniazid-pyrazinamide (RHZ) regimen, whereas, between November of 2010 and June of 2013, the patients were treated with the rifampin-isoniazid-pyrazinamide-ethambutol FDC (RHZE/FDC) regimen. Data regarding tuberculosis recurrence and mortality in the patients studied were retrieved from the Brazilian Case Registry Database and the Brazilian Mortality Database, respectively. The follow-up period comprised two years after treatment completion. Results:: The rates of cure, treatment abandonment, and death were 90.4%, 4.8%, and 4.8%, respectively. There were 7 cases of recurrence during the follow-up period. No significant differences in the recurrence rate were found between the RHZ and RHZE/FDC regimen groups (p = 0.13). We identified no factors associated with the occurrence of recurrence; nor were there any statistically significant differences between the treatment groups regarding adverse effects or rates of cure, treatment abandonment, or death. Conclusions:: The adoption of the RHZE/FDC regimen produced no statistically significant differences in the rates of recurrence, cure, or treatment abandonment; nor did it have any effect on the occurrence of adverse effects, in comparison with the use of the RHZ regimen. Objetivo:: Estimar as taxas de recidiva, cura e abandono de tratamento em pacientes com tuberculose pulmonar tratados com o esquema de dose fixa combinada (DFC) de quatro drogas e avaliar possíveis fatores associados. Métodos:: Estudo observacional retrospectivo com 208 pacientes com diagnóstico confirmado de tuberculose pulmonar registrados no Programa de Controle da Tuberculose Hospitalar do Instituto de Doenças do Tórax, localizado na cidade do Rio de Janeiro. Os pacientes tratados entre janeiro de 2007 e outubro de 2010 receberam o esquema rifampicina-isoniazida-pirazinamida (RHZ), e aqueles tratados entre novembro de 2010 e junho de 2013 receberam o esquema rifampicina-isoniazida-pirazinamida-etambutol em DFC (RHZE/DFC). Os dados dos pacientes sobre recidiva e óbito foram obtidos no Sistema de Informação de Agravos de Notificação e no Sistema de Informação de Mortalidade, respectivamente. O período de acompanhamento foi de dois anos após o encerramento do tratamento. Resultados:: As taxas de cura, abandono e óbito foram de 90,4%, 4,8% e 4,8%, respectivamente. Houve 7 casos de recidivas durante o período de acompanhamento. Não houve diferenças significativas na taxa de recidiva entre os grupos de tratamento RHZ e RHZE/DFC (p = 0,13). Não foram identificados fatores associados com a ocorrência de recidiva, nem houve diferenças estatisticamente significativas na ocorrência dos efeitos adversos ou nas taxas de cura, abandono e óbito entre os grupos de tratamento. Conclusões:: A adoção do esquema de tratamento RHZE/DFC não produziu diferenças estatisticamente significativas nas taxas de recidiva, cura e abandono nem na ocorrência de efeitos adversos em comparação com o esquema RHZ.
[Mh] Termos MeSH primário: Antibióticos Antituberculose/uso terapêutico
Tuberculose Pulmonar/tratamento farmacológico
Tuberculose Pulmonar/epidemiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Antibióticos Antituberculose/classificação
Brasil/epidemiologia
Cidades/epidemiologia
Quimioterapia Combinada/métodos
Etambutol/uso terapêutico
Feminino
Seres Humanos
Incidência
Isoniazida/uso terapêutico
Masculino
Meia-Idade
Pirazinamida/uso terapêutico
Recidiva
Estudos Retrospectivos
Rifampina/uso terapêutico
Fatores de Risco
Tuberculose Pulmonar/diagnóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Antibiotics, Antitubercular); 2KNI5N06TI (Pyrazinamide); 8G167061QZ (Ethambutol); V83O1VOZ8L (Isoniazid); VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170525
[St] Status:MEDLINE


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[PMID]:28501621
[Au] Autor:Adachi R; Okada K; Skene R; Ogawa K; Miwa M; Tsuchinaga K; Ohkubo S; Henta T; Kawamoto T
[Ad] Endereço:Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: ryutaro_adachi@hotmail.com.
[Ti] Título:Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with l-proline.
[So] Source:Biochem Biophys Res Commun;488(2):393-399, 2017 Jun 24.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family of enzymes and catalyzes the synthesis of prolyl-tRNA using ATP, l-proline, and tRNA as substrates. An ATP-dependent PRS inhibitor, halofuginone, was shown to suppress autoimmune responses, suggesting that the inhibition of PRS is a potential therapeutic approach for inflammatory diseases. Although a few PRS inhibitors have been derivatized from natural sources or substrate mimetics, small-molecule human PRS inhibitors have not been reported. In this study, we discovered a novel series of pyrazinamide PRS inhibitors from a compound library using pre-transfer editing activity of human PRS enzyme. Steady-state biochemical analysis on the inhibitory mode revealed its distinctive characteristics of inhibition with proline uncompetition and ATP competition. The binding activity of a representative compound was time-dependently potentiated by the presence of l-proline with K of 0.76 nM. Thermal shift assays demonstrated the stabilization of PRS in complex with l-proline and pyrazinamide PRS inhibitors. The binding mode of the PRS inhibitor to the ATP site of PRS enzyme was elucidated using the ternary complex crystal structure with l-proline. The results demonstrated the different inhibitory and binding mode of pyrazinamide PRS inhibitors from preceding halofuginone. Furthermore, the PRS inhibitor inhibited intracellular protein synthesis via a different mode than halofuginone. In conclusion, we have identified a novel drug-like PRS inhibitor with a distinctive binding mode. This inhibitor was effective in a cellular context. Thus, the series of PRS inhibitors are considered to be applicable to further development with differentiation from preceding halofuginone.
[Mh] Termos MeSH primário: Trifosfato de Adenosina/metabolismo
Aminoacil-tRNA Sintetases/antagonistas & inibidores
Descoberta de Drogas
Inibidores Enzimáticos/farmacologia
Prolina/metabolismo
Pirazinamida/farmacologia
[Mh] Termos MeSH secundário: Aminoacil-tRNA Sintetases/metabolismo
Sítios de Ligação/efeitos dos fármacos
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Células HEK293
Seres Humanos
Estrutura Molecular
Pirazinamida/síntese química
Pirazinamida/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 2KNI5N06TI (Pyrazinamide); 8L70Q75FXE (Adenosine Triphosphate); 9DLQ4CIU6V (Proline); EC 6.1.1.- (Amino Acyl-tRNA Synthetases); EC 6.1.1.15 (prolyl T RNA synthetase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170515
[St] Status:MEDLINE


  9 / 2666 MEDLINE  
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[PMID]:28275074
[Au] Autor:Votintseva AA; Bradley P; Pankhurst L; Del Ojo Elias C; Loose M; Nilgiriwala K; Chatterjee A; Smith EG; Sanderson N; Walker TM; Morgan MR; Wyllie DH; Walker AS; Peto TEA; Crook DW; Iqbal Z
[Ad] Endereço:Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom a.votintseva@gmail.com zam@well.ox.ac.uk.
[Ti] Título:Same-Day Diagnostic and Surveillance Data for Tuberculosis via Whole-Genome Sequencing of Direct Respiratory Samples.
[So] Source:J Clin Microbiol;55(5):1285-1298, 2017 May.
[Is] ISSN:1098-660X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Routine full characterization of is culture based, taking many weeks. Whole-genome sequencing (WGS) can generate antibiotic susceptibility profiles to inform treatment, augmented with strain information for global surveillance; such data could be transformative if provided at or near the point of care. We demonstrate a low-cost method of DNA extraction directly from patient samples for WGS. We initially evaluated the method by using the Illumina MiSeq sequencer (40 smear-positive respiratory samples obtained after routine clinical testing and 27 matched liquid cultures). was identified in all 39 samples from which DNA was successfully extracted. Sufficient data for antibiotic susceptibility prediction were obtained from 24 (62%) samples; all results were concordant with reference laboratory phenotypes. Phylogenetic placement was concordant between direct and cultured samples. With Illumina MiSeq/MiniSeq, the workflow from patient sample to results can be completed in 44/16 h at a reagent cost of £96/£198 per sample. We then employed a nonspecific PCR-based library preparation method for sequencing on an Oxford Nanopore Technologies MinION sequencer. We applied this to cultured strain BCG DNA and to combined culture-negative sputum DNA and BCG DNA. For flow cell version R9.4, the estimated turnaround time from patient to identification of BCG, detection of pyrazinamide resistance, and phylogenetic placement was 7.5 h, with full susceptibility results 5 h later. Antibiotic susceptibility predictions were fully concordant. A critical advantage of MinION is the ability to continue sequencing until sufficient coverage is obtained, providing a potential solution to the problem of variable amounts of DNA in direct samples.
[Mh] Termos MeSH primário: Antituberculosos/uso terapêutico
Genoma Bacteriano/genética
Mycobacterium tuberculosis/genética
Análise de Sequência de DNA/métodos
Tuberculose Pulmonar/diagnóstico
[Mh] Termos MeSH secundário: Sequenciamento de Nucleotídeos em Larga Escala/economia
Seres Humanos
Testes de Sensibilidade Microbiana
Mycobacterium tuberculosis/efeitos dos fármacos
Sistemas Automatizados de Assistência Junto ao Leito
Pirazinamida/uso terapêutico
Fatores de Tempo
Tuberculose Pulmonar/tratamento farmacológico
Tuberculose Pulmonar/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 2KNI5N06TI (Pyrazinamide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE
[do] DOI:10.1128/JCM.02483-16


  10 / 2666 MEDLINE  
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[PMID]:28244290
[Au] Autor:Mok JH; Kang BH; Lee T; Lee HK; Jang HJ; Cho YJ; Jeon D
[Ad] Endereço:Department of Internal Medicine, Pusan National University Hospital, Busan, Korea.
[Ti] Título:Additional Drug Resistance Patterns among Multidrug-Resistant Tuberculosis Patients in Korea: Implications for Regimen Design.
[So] Source:J Korean Med Sci;32(4):636-641, 2017 Apr.
[Is] ISSN:1598-6357
[Cp] País de publicação:Korea (South)
[La] Idioma:eng
[Ab] Resumo:Detailed information on additional drug resistance patterns of multidrug-resistant tuberculosis (MDR-TB) is essential to build an effective treatment regimen; however, such data are scarce in Korea. We retrospectively analyzed the results of phenotypic drug susceptibility testing (DST) of culture confirmed-TB patients from January 2010 to December 2014 in 7 university hospitals in Korea. MDR-TB was identified among 6.8% (n = 378) of 5,599 isolates. A total of 57.1% (n = 216) of the MDR-TB patients had never been treated for TB. Strains from MDR-TB patients showed additional resistance to pyrazinamide (PZA) (35.7%), any second-line injectable drug (19.3%), and any fluoroquinolone (26.2%). Extensively drug resistant TB comprised 12.4% (n = 47) of the MDR-TB patients. Of 378 MDR-TB patients, 50.3% (n = 190) were eligible for the shorter MDR-TB regimen, and 50.0% (n = 189) were fully susceptible to the 5 drugs comprising the standard conventional regimen (PZA, kanamycin, ofloxoacin, prothionamide, and cycloserine). In conclusion, the proportion of new patients and the levels of additional drug resistance were high in MDR-TB patients. Considering the high levels of drug resistance, the shorter MDR-TB treatment regimen may not be feasible; instead, an individually tailored regimen based on the results of molecular and phenotypic DST may be more appropriate in MDR-TB patients in Korea.
[Mh] Termos MeSH primário: Antituberculosos/uso terapêutico
Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Antituberculosos/farmacologia
Criança
Pré-Escolar
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos
Feminino
Fluoroquinolonas/uso terapêutico
Seres Humanos
Lactente
Recém-Nascido
Masculino
Meia-Idade
Mycobacterium tuberculosis/efeitos dos fármacos
Mycobacterium tuberculosis/isolamento & purificação
Pirazinamida/uso terapêutico
República da Coreia/epidemiologia
Estudos Retrospectivos
Centros de Atenção Terciária
Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Fluoroquinolones); 2KNI5N06TI (Pyrazinamide)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170523
[Lr] Data última revisão:
170523
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE
[do] DOI:10.3346/jkms.2017.32.4.636



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