Open AccessRole of the ABC Transporter MRPA (PGPA) in Antimony Resistance in Leishmania infantum Axenic and Intracellular Amastigotes
Author(s) -
Karima El Fadili,
Nadine Messier,
Philippe Leprohon,
Gaétan Roy,
Chantal Guimond,
Nathalie Trudel,
Nancy Gore Saravia,
Barbara Papadopoulou,
Danielle Légaré,
Marc Ouellette
Publication year - 2005
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.49.5.1988-1993.2005
Subject(s) - leishmania infantum , axenic , amastigote , intracellular , microbiology and biotechnology , leishmania , atp binding cassette transporter , transporter , kinetoplastida , drug resistance , biology , chemistry , leishmaniasis , biochemistry , bacteria , gene , parasite hosting , immunology , visceral leishmaniasis , protozoal disease , genetics , world wide web , computer science , malaria
Antimonial compounds are the mainstay for the treatment of infections with the protozoan parasite Leishmania. We present our studies on Leishmania infantum amastigote parasites selected for resistance to potassium antimonyl tartrate [Sb(III)]. Inside macrophages, the Sb(III)-selected cells are cross-resistant to sodium stibogluconate (Pentostam), the main drug used against Leishmania. Putative alterations in the level of expression of more than 40 genes were compared between susceptible and resistant axenic amastigotes using customized DNA microarrays. The expression of three genes coding for the ABC transporter MRPA (PGPA), S-adenosylhomocysteine hydrolase, and folylpolyglutamate synthase was found to be consistently increased. The levels of cysteine were found to be increased in the mutant. Transfection of the MRPA gene was shown to confer sodium stibogluconate resistance in intracellular parasites. This MRPA-mediated resistance could be reverted by using the glutathione biosynthesis-specific inhibitor buthionine sulfoximine. These results highlight for the first time the role of MRPA in antimony resistance in the amastigote stage of the parasite and suggest a strategy for reversing resistance.