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Comprehensive analysis of resistance development in the malaria parasite

Corey, Victoria and Fuchs, Olivia and Meister, Stephan and Goldgof, Greg and Winzeler, Elizabeth and Istvan, Eva and Goldberg, Daniel and Coburn-Flynn, Olivia and Gnadig, Nina and Lee, Marcus and Fidock, David and Sakata-Kato, Tomoyo and Lukens, Amanda and Magistrado, Pamela and Wirth, Dyann and Linares, Maria and Franco, Virginia and Gracia, Maria and Gamo, Francisco and Zhou, Yingyao and Tanaseichuk, Olga (2016) Comprehensive analysis of resistance development in the malaria parasite. Nature communications, 7 (1). pp. 1-9. ISSN 2041-1723

Abstract

Using a diverse set of antimalarial compounds with activity against asexual blood stage P. falciparum parasites, we have systematically investigated both the acquisition of drug resistance and the extent to which common drug resistance alleles confer resistance. We assessed the landscape of cross-resistance using a set of 16 parasites lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, proline t-RNA ligase, or hsp90. In addition, we assessed whether resistant parasites could be obtained after several months of selection. Our data show that patterns of resistance were compound-specific and no strains were universally resistant to all chemicals. We also observed that some mutations, including those in pfatp4, sensitized strains to the action of antimalarial compounds. Evaluation of different chemical characteristics, including physiochemical and structural features, predicted transmission-blocking and causal prophylactic activity, and parasite killing rate. We found that it was more difficult to obtain resistant parasites for fast killing compounds, and that existing drug resistant alleles were antimalarial specific. Our data show that the notion that pre-existing resistance is not a major burden to antimalarial candidates that have novel targets, and that focusing our attention on fast killing compounds that may result in a slower onset of resistance in the clinic.

Item Type: Article
Keywords: Malaria, Plasmodium falciparum, cross resistance, selection, killing rate, multistage activity, mutation, antimalarials, drug development
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/27349

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