Changes in the infectivity, pyruvate kinase activity, acid phosphatase activity and P-glycoprotein expression in glibenclamide-resistant Leishmania mexicana.
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 for both 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 suggested a mechanism to overcome the effect of glibenclamide.
García
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N
Laboratory of Molecular Physiology, Instituto de Medicina Experimental, Facultad de Medicina, Universidad Central de Venezuela, Caracas.
Figarella
K
K
Mendoza-León
A
A
Ponte-Sucre
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003470:Culture Media; D004351:Drug Resistance; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007894:Leishmania mexicana / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D016773:Leishmaniasis, Cutaneous / Q000469:parasitology; D008264:Macrophages / Q000469:parasitology; D011770:Pyruvate Kinase / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003470:Culture Media; D011770:Pyruvate Kinase; D000135:Acid Phosphatase; D005905:Glyburide