Construção de um painel com isolados clínicos de Mycobacterium tuberculosis com genes de resistência a quimioterápicos, para o estudo de novas drogas anti-TB
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Data
2010-11-29
Autores
Miyata, Marcelo [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
De acordo com a Organização Mundial de Saúde em 2009, 9,27 milhões de novos casos de tuberculose ocorreram em 2007. Destes novos casos, 4,9% eram multidroga resistentes. Muitas pesquisas são realizadas na procura de novas drogas com atividade contra o bacilo da tuberculose, havendo então a necessidade de se entender os mecanismos de ação destes novos compostos. Este projeto objetivou propiciar ferramentas para compreender um pouco mais sobre os mecanismos de ação de novas drogas. Isolados clínicos de M. tuberculosis foram caracterizados quanto ao seu perfil de susceptibilidade aos fármacos do esquema terapêutico e foram determinadas as mutações responsáveis por estas resistências. Com os isolados caracterizados, foi construído um painel de M. tuberculosis. Pelo REMA, os isolados foram analisados quanto ao seu perfil de susceptibilidade aos fármacos (INH, RMP, STR e ETB) e avaliados quanto à presença de mutações nos genes de resistência (inhA, katG, ahpC, rpoβ, rpsL, rrs e embB) empregando a PCR-SSCP. Pelo REMA foram avaliados 80 isolados clínicos, sendo observada a resistência a INH em 74,7%, a RMP em 51,2%, a STR em 53,7% e ao ETB em 58,7%. Nos isolados resistentes, a porcentagem de mutações encontradas nos genes foi de 20,6% para inhA, 50% para katG, 6,3% para ahpC, 60% para rpoβ, 20% para rpsL e 0% para rrs e embB. Um painel com 12 isolados foi testado frente a três novos compostos, dois derivados de INH (Cu-INH1 e Cu-INH2) e um de RMP (Cu-RMP). Verificou-se que os isolados resistentes a INH foram também resistentes a Cu-INH1 e Cu-INH2. A mesma situação foi verificada em relação à RMP, com o composto Cu-RMP. Provavelmente, estes novos compostos têm os mesmos mecanismos de ação da INH e da RMP, que são os fármacos que lhes deram origem
According to World Health Organization in 2009, 9.27 million new TB cases occurred in 2007. Among these new cases, 4.9% were multidrug resistant. Many surveys are conducted in the search for new drugs with activity against the tuberculosis bacillus, therefore there is a need to understand the action mechanism of these new compounds. This project aimed to provide tools to understand about the action mechanisms of new drugs. M. tuberculosis clinical isolates were analyzed for their susceptibility profile to drugs, mutations responsible for resistance and a panel of these characterized isolates. The isolates were analyzed for susceptibility profile to drugs (INH, RIF, STR and ETB) and evaluated for presence of mutations in the resistance genes (inhA, katG, ahpC, rpoβ, rpsL, rrs and embB) applying the PCR-SSCP. REMA evaluated 85 clinical isolates and the resistance was observed in 74.7% to INH, 51.5% to RIF, 53.7% to STR and 58.7% to ETB. In the resistant isolates, percentage of mutations found in the genes was 20.6% for inhA, 50% for katG, 6.3% for ahpC, 60% for rpoβ, 20% for rpsL and 0% for rrs and embB. A panel of 12 isolates was tested against three new compounds, two INH-derivatives (Cu-INH1 and Cu-INH2) and one RMP-derivative (Cu-RMP). The isolates resistant to INH were also resistant to Cu-INH1 and Cu-INH2 compounds. The same situation was verified in relation to the RMP with the Cu-RMP compound, indicating that probably these three new compounds have the same action mechanism of INH and RMP drugs
According to World Health Organization in 2009, 9.27 million new TB cases occurred in 2007. Among these new cases, 4.9% were multidrug resistant. Many surveys are conducted in the search for new drugs with activity against the tuberculosis bacillus, therefore there is a need to understand the action mechanism of these new compounds. This project aimed to provide tools to understand about the action mechanisms of new drugs. M. tuberculosis clinical isolates were analyzed for their susceptibility profile to drugs, mutations responsible for resistance and a panel of these characterized isolates. The isolates were analyzed for susceptibility profile to drugs (INH, RIF, STR and ETB) and evaluated for presence of mutations in the resistance genes (inhA, katG, ahpC, rpoβ, rpsL, rrs and embB) applying the PCR-SSCP. REMA evaluated 85 clinical isolates and the resistance was observed in 74.7% to INH, 51.5% to RIF, 53.7% to STR and 58.7% to ETB. In the resistant isolates, percentage of mutations found in the genes was 20.6% for inhA, 50% for katG, 6.3% for ahpC, 60% for rpoβ, 20% for rpsL and 0% for rrs and embB. A panel of 12 isolates was tested against three new compounds, two INH-derivatives (Cu-INH1 and Cu-INH2) and one RMP-derivative (Cu-RMP). The isolates resistant to INH were also resistant to Cu-INH1 and Cu-INH2 compounds. The same situation was verified in relation to the RMP with the Cu-RMP compound, indicating that probably these three new compounds have the same action mechanism of INH and RMP drugs
Descrição
Palavras-chave
Tuberculose, DNA, Mycobacterium tuberculosis, Tuberculosis
Como citar
MIYATA, Marcelo. Construção de um painel com isolados clínicos de Mycobacterium tuberculosis com genes de resistência a quimioterápicos, para o estudo de novas drogas anti-TB. 2010. 119 f +. Tese (doutorado) - Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas, 2010.