Changes in the infectivity, pyruvate kinase and acid phosphatase activity and p-glycoprotein expression in glibenclamide resistant Leishmania mexicana

Abstract

We previously demonstrated susceptibility of Leishmania sp. to glibenclamide, a K+-ATP transport blocker, which interacts with members of the superfamily of adenosine 5’ triphosphate binding cassette transporters. In order to characterize the molecular differences between a sensitive Leishmania strain, NR(Gs), and an experimentally selected glibenclamide resistant strain, NR(Gr), specific biochemical and functional parameters have been evaluated both in the wild type and in the resistant strain. Most noteworthy, NR(Gr) exhibit an increased expression of P-glycoprotein and a decreased activity of functional key enzymes such as acid phosphatase, a prominent virulent factor of the parasite, and pyruvate kinase, a key control enzyme both for the carbohydrate and protein metabolism. The specific biochemical, metabolic and functional changes observed in the resistant strain correlated with a reduced infectivity of stationary phase NR(Gr) in J774 macrophages, and suggest a mechanism to overcome the effect of glibenclamide.