A broad analysis of resistance development in the malaria parasite
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Date
2016
Author(s)
Corey, Victoria C.
Istvan, Eva S.
Lee, Marcus C. S.
Franco, Virginia
Coburn-Flynn, Olivia
Sakata-Kato, Tomoyo
Fuchs, Olivia
Gnädig, Nina F.
Goldgof, Greg
Linares, Maria
Gomez-Lorenzo, Maria G.
De Cózar, Cristina
Lafuente-Monasterio, Maria Jose
Prats, Sara
Meister, Stephan
Tanaseichuk, Olga
Wree, Melanie
Zhou, Yingyao
Willis, Paul A.
Gamo, Francisco-Javier
Goldberg, Daniel E.
Fidock, David A.
Winzeler, Elizabeth A.
Publisher
Nature Publishing Group
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Citation
Corey, V. C., A. K. Lukens, E. S. Istvan, M. C. S. Lee, V. Franco, P. Magistrado, O. Coburn-Flynn, et al. 2016. “A broad analysis of resistance development in the malaria parasite.” Nature Communications 7 (1): 11901. doi:10.1038/ncomms11901. http://dx.doi.org/10.1038/ncomms11901.
Abstract
Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance.
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