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Previous issue date: 2012-05-16 / Tuberculosis continues to be one of the deadliest diseases in the world. The emergence of drug-resistant strains of Mycobacterium tuberculosis, the unbearable side effects of the available drugs and the frequent patient non-compliance in completing the therapy have increased the need for development of new effective agents. We have previously demonstrated a potent in vitro inhibitory activity for two pentacyano(isoniazid)ferrate(II) compounds, namely IQG-607 and IQG-639 against the M. tuberculosis enoyl-ACP reductase enzyme. Importantly, IQG-607 and IQG-639 were active against cultures of M. tuberculosis H37Rv and two isoniazid-resistant clinical isolates in vitro. In the present study, the activity of these compounds was evaluated by using an in vivo murine model of tuberculosis. Swiss mice were infected with M. tuberculosis H37Rv strain, and IQG-607 and IQG-639 (250 mg/kg) were administered during 28 or 56 days. As well, a dose-response study was performed with IQG-607 (at 5, 10, 25, 50, 100, 200 and 250 mg/kg). The activity of test compounds was compared with that of the positive control drug isoniazid at 25 mg/kg. After 28 or 56 days of treatment, either IQG-607 or isoniazid significantly reduced M. tuberculosis-induced splenomegaly, and also significantly diminished the colony-forming units in both spleens and lungs. IQG-607 or isoniazid ameliorated the lung macroscopic aspect, reducing the lung lesions to a similar extent. However, IQG-639 was not capable of significantly modifying any evaluated parameter. IQG-607 did not display a classical dose-dependent profile in our murine model of tuberculosis, and 10 mg/kg was the lowest dose able to show significant activity, which was similar to the inhibition observed for higher doses. In addition, experiments using early and late controls of infection revealed a bactericidal activity for IQG-607 in our model. The promising activity of IQG-607 in M. tuberculosis-infected mice suggests that this compound might represent a good candidate for clinical development as a new antimycobacterial agent. / A tuberculose ? uma das principais causas de morte no mundo. O surgimento e dissemina??o de cepas de Mycobacterium tuberculosis resistentes a f?rmacos, os efeitos indesej?veis dos f?rmacos atualmente dispon?veis e a falta de ades?o dos pacientes ao tratamento t?m aumentado a necessidade do desenvolvimento de novos agentes anti-tuberculose. Estudos pr?vios revelaram uma potente atividade inibit?ria in vitro de dois compostos pentaciano(isoniazida)ferrato(II), denominados IQG-607 e IQG- 639, frente a enzima enoil-ACP redutase de M. tuberculosis. Ainda, o IQG- 607 e o IQG-639 foram ativos quando testados em culturas de M. tuberculosis H37Rv e sobre dois isolados cl?nicos resistentes ? isoniazida in vitro. Neste trabalho, a atividade destes dois compostos foi avaliada in vivo, utilizando um modelo murino de infec??o por M. tuberculosis. Camundongos su??os foram infectados com a cepa de M. tuberculosis H37Rv e o IQG-607 ou o IQG-639 (250 mg/kg) foram administrados aos animais durante 28 ou 56 dias. Adicionalmente, um estudo de dose-resposta foi realizado com o composto IQG-607, empregando as doses de 5, 10, 25, 50, 100, 200 e 250 mg/kg. As atividades dos compostos-teste foram comparadas ? atividade da isoniazida (25 mg/kg), o controle positivo do tratamento. Ap?s 28 ou 56 dias de tratamento, tanto o IQG-607 quanto a isoniazida reduziram significativamente a esplenomegalia induzida pela infec??o e, tamb?m, diminu?ram as unidades formadoras de col?nia, tanto nos pulm?es quanto nos ba?os dos animais tratados. O IQG-607 e a isoniazida melhoraram o aspecto macrosc?pico dos pulm?es, reduzindo as les?es pulmonares de maneira semelhante. Por sua vez, o IQG-639 n?o foi capaz de modificar significativamente nenhum par?metro avaliado neste estudo. O IQG-607 n?o apresentou um perfil cl?ssico de dose depend?ncia, sendo observada atividade inibit?ria significativa similar, entre as doses de 10 mg/kg e 250 mg/kg. Al?m disto, um experimento utilizando um controle pr?-tratamento demonstrou que o IQG-607 possui atividade bactericida no nosso modelo. A atividade satisfat?ria do IQG-607 em camundongos infectados com M. tuberculosis sugere que este composto pode ser um candidato promissor no desenvolvimento cl?nico de um novo agente antimicobacteriano.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/1695 |
| Date | 16 May 2012 |
| Creators | Rodrigues Junior, Valn?s da Silva |
| Contributors | Campos, Maria Martha |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Medicina e Ci?ncias da Sa?de, PUCRS, BR, Faculdade de Medicina |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 7620745074616285884, 500, 600, -8624664729441623247 |
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