Glibenclamide modulates glucantime activity and disposition in Leishmania major.
A source of chemotherapeutic failure in anti-infective therapies is the active movement of drugs across membranes, through ATP-binding cassette (ABC) transporters. In fact, simultaneous administration of therapeutic drugs with ABC transporter blockers has been invoked to be the way to actively prevent the emergence of drug resistance. Herein, we demonstrate that glucantime's efficacy in decreasing the infection rate of Leishmania-infected macrophages is strongly enhanced when used in combination with glibenclamide, a specific blocker of ABC transporters. Intracellular ABC transporters mediate glucantime sequestration in intracellular organelles. Their selective inhibition may effectively increase the cytoplasmic concentration of glucantime and its leishmanicidal activity. Our results reveal for the first time that glibenclamide targets in Leishmania major a compartment associated with a multivesicular system that is simultaneously labeled by the acidic marker LysoTracker-red and may represent the organelle where antimonials are sequestered. These results constitute a proof of concept that conclusively demonstrates the potential value that combination therapy with an ABC transporter blocker may have for leishmaniasis therapy.
Padrón-Nieves
Maritza
M
Laboratorio de Fisiología Molecular, Instituto de Medicina Experimental, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela.
Díaz
Emilia
E
Machuca
Claudia
C
Romero
Amarilis
A
Ponte Sucre
Alicia
A
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D004357:Drug Synergism; D005905:Glyburide / Q000378:metabolism / Q000494:pharmacology*; D018320:Leishmania major / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D017737:Macrophages, Peritoneal / Q000469:parasitology; D008536:Meglumine / Q000378:metabolism / Q000494:pharmacology*; D000077485:Meglumine Antimoniate; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D008536:Meglumine; D000077485:Meglumine Antimoniate; D000666:Amphotericin B; D005905:Glyburide