A broad analysis of resistance development in the malaria parasite

Victoria C. Corey, Amanda K. Lukens, Eva S. Istvan, Marcus C.S. Lee, Virginia Franco, Pamela Magistrado, Olivia Coburn-Flynn, Tomoyo Sakata-Kato, Olivia Fuchs, Nina F. Gnädig, Greg Goldgof, Maria Linares, Maria G. Gomez-Lorenzo, Cristina De Cózar, Maria Jose Lafuente-Monasterio, Sara Prats, Stephan Meister, Olga Tanaseichuk, Melanie Wree, Yingyao ZhouPaul A. Willis, Francisco Javier Gamo, Daniel E. Goldberg, David A. Fidock, Dyann F. Wirth, Elizabeth A. Winzeler

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49 Scopus citations

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 bc 1, 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.

Original languageEnglish
Article number11901
JournalNature communications
Volume7
DOIs
StatePublished - Jun 15 2016

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    Corey, V. C., Lukens, A. K., Istvan, E. S., Lee, M. C. S., Franco, V., Magistrado, P., Coburn-Flynn, O., Sakata-Kato, T., Fuchs, O., Gnädig, N. F., Goldgof, G., Linares, M., Gomez-Lorenzo, M. G., De Cózar, C., Lafuente-Monasterio, M. J., Prats, S., Meister, S., Tanaseichuk, O., Wree, M., ... Winzeler, E. A. (2016). A broad analysis of resistance development in the malaria parasite. Nature communications, 7, [11901]. https://doi.org/10.1038/ncomms11901