Leishmania amazonensis: Metabolic adaptations induced by resistance to an ABC transporter blocker

Abstract

We compared growth rate, cell glucose turnover and expression of ATP-binding-cassette (ABC) transporters in Leishmania amazonensis (LTB0016; LTB) versus LTB160 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) LTB160 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) LTB160 parasites use less glucose as energy substrate and exhibit a slower glucose uptake than LTB cells and 4) LTB160 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 LTB160 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.