Leishmania amazonensis: metabolic adaptations induced by resistance to an ABC transporter blocker.
We compared growth rate, cell glucose turnover and expression of ATP-binding-cassette (ABC) transporters in Leishmania amazonensis (LTB0016; LTB) versus LTB(160) selected for resistance against the ABC transporter blocker glibenclamide. Additionally, we evaluated the influence of drug-resistance on Leishmania sensitivity against 2-mercaptoacetate and 2-deoxyglucose. Our data demonstrate that (1) LTB(160) and LTB constitutively express ABC transporters for neutral substrates, (2) glibenclamide resistance induces the expression of organic anion ABC transporters, members of the drug resistance associated transporters subfamily, (3) LTB(160) parasites use less glucose as energy substrate and exhibit a slower glucose uptake than LTB cells, and (4) LTB(160) parasites are less sensitive to 2-mercaptoacetate and 2-deoxyglucose than the glibenclamide-sensitive Leishmania LTB. Together these and previous results indicate that the metabolic adaptations expressed in drug-resistant LTB(160) differ from those described for mammalian drug resistant cells and constitute general mechanisms that underlie drug resistance in Leishmania and may be helpful for identifying alternative strategies to circumvent drug resistance in leishmaniasis.
Laboratory of Molecular Physiology, Instituto de Medicina Experimental, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela.
Claudia
C
Machuca
Adriana
A
Rodríguez
Marymar
M
Herrera
Sonia
S
Silva
Alicia
A
Ponte-Sucre
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000222:Adaptation, Physiological; D000818:Animals; D003847:Deoxyglucose / Q000494:pharmacology; D004351:Drug Resistance / Q000502:physiology*; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology*; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D013864:Thioglycolates / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D003847:Deoxyglucose; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005947:Glucose; D005905:Glyburide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013864:Thioglycolates; C085925:calcein AM; C017487:2-mercaptoacetate; C007740:fluorexon