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Doctoral Thesis
DOI
10.11606/T.42.2007.tde-20102008-182715
Document
Author
Full name
Adriano Cappellazzo Coelho
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2007
Supervisor
Committee
Cotrim, Paulo Cesar (President)
Silveira Filho, José Franco da
Tosi, Luiz Ricardo Orsini
Uliana, Silvia Reni Bortolin
Winter, Lucile Maria Floeter
Title in Portuguese
Papel do transportador ABC PRP1 na resistência à pentamidina em Leishmania spp.
Keywords in Portuguese
Leishmania
Pentamidina
Resistência à drogas
Transfecção gênica
Transportador ABC
Abstract in Portuguese
Pouco se sabe sobre o mecanismo de ação da pentamidina, um composto utilizado no tratamento das leishmanioses. Para uma melhor compreensão do mecanismo de ação assim como o mecanismo de resistência à pentamidina, foi isolado um gene que codifica um membro da família de transportadores ABC, chamado PRP1 capaz de conferir resistência à pentamidina em formas promastigotas e amastigotas de Leishmania spp. O tratamento dos transfectantes que superexpressam a PRP1 com pentamidina em presença de concentrações não tóxicas de verapamil, um inibidor de transportadores ABC, foi capaz de reverter a resistência mediada por esse transportador. Foram ainda isolados nesse estudo duas linhagens de L. amazonensis resistentes à pentamidina. A análise molecular dos parasitos indicou que esses mutantes não apresentaram nenhuma amplificação de DNA, inclusive do gene PRP1 que também não se mostrou superexpresso em ambas as linhagens. As duas linhagens resistentes à pentamidina tiveram sua resistência revertida quando tratadas com verapamil, indicando que o mecanismo de resistência nesses mutantes pode estar associado a um transportador ABC. Os resultados obtidos nesse estudo fornecem dados para uma melhor compreensão do mecanismo de resistência à pentamidina e sugerem um provável potencial da associação pentamidina e verapamil no tratamento da doença.
Title in English
Role of the ABC transporter PRP1 in pentamidine resistance in Leishmania spp.
Keywords in English
Leishmania
ABC transporter
Pentamidine
Resistance to drugs
Transfecção gene
Abstract in English
Little it is known about the mechanism of action of pentamidine, an compound used for leishmaniases chemotherapy. To understand the mechanism of action and resistance of pentamidine, it was isolated a gene that codifies a member of ABC transporter family, named as PRP1 able to confer pentamidine resistance in promastigotes and amastigotes of Leishmania spp. Treatment of transfectants overexpressing PRP1 with pentamidine in presence of non toxic concentration of verapamil, an inhibitor of ABC transporters, was able to reverse the drug resistance mediated by this transporter. Two lines of L. amazonensis resistant to pentamidine were selected. Molecular analysis of parasites indicated that these mutants do not contain amplified DNA, including the PRP1 gene either not associated with overexpression in both lines. The two lines resistant to pentamidine had their resistance reversed when treated with verapamil, indicating that the mechanism of resistance may be associated to an ABC transporter. The results of this work lead to new insights for a better understanding of the mechanism of of resistance suggesting a probably potencial of pentamidine and verapamil association in the chemotherapy.
 
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Publishing Date
2008-10-21
 
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