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 (Lead / Corresponding author)

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84 Citations (Scopus)
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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
Number of pages9
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 15 Jun 2016

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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