Publication
Title
Experimental resistance to drug combinations in Leishmania donovani : metabolic and phenotypic adaptations
Author
Abstract
Together with vector control, chemotherapy is an essential tool for the control of visceral leishmaniasis (VL), but its efficacy is jeopardized by growing resistance and treatment failure against first-line drugs. To delay the emergence of resistance, the use of drug combinations of existing antileishmanial agents has been tested systematically in clinical trials for the treatment of visceral leishmaniasis (VL). In vitro, Leishmania donovani promastigotes are able to develop experimental resistance to several combinations of different antileishmanial drugs after 10 weeks of drug pressure. Using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach, we identified metabolic changes in lines that were experimentally resistant to drug combinations and their respective single-resistant lines. This highlighted both collective metabolic changes (found in all combination therapy-resistant [CTR] lines) and specific ones (found in certain CTR lines). We demonstrated that single-resistant and CTR parasite cell lines show distinct metabolic adaptations, which all converge on the same defensive mechanisms that were experimentally validated: protection against drug-induced and external oxidative stress and changes in membrane fluidity. The membrane fluidity changes were accompanied by changes in drug uptake only in the lines that were resistant against drug combinations with antimonials, and surprisingly, drug accumulation was higher in these lines. Together, these results highlight the importance and the central role of protection against oxidative stress in the different resistant lines. Ultimately, these phenotypic changes might interfere with the mode of action of all drugs that are currently used for the treatment of VL and should be taken into account in drug development.
Language
English
Source (journal)
Antimicrobial agents and chemotherapy. - Washington, D.C.
Publication
Washington, D.C. : 2015
ISSN
0066-4804
Volume/pages
59:4(2015), p. 2242-2255
ISI
000354993700050
Full text (Publishers DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Publication type
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Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
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Creation 19.05.2016
Last edited 02.05.2017
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