A broad analysis of resistance development in the malaria parasite.

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Journal:
Nature communications, Volume: 7
Published:
June 15, 2016
PMID:
27301419
Authors:
Victoria C Corey VC, Amanda K Lukens AK, Eva S Istvan ES, Marcus C S Lee MCS, Virginia Franco V, Pamela Magistrado P, Olivia Coburn-Flynn O, Tomoyo Sakata-Kato T, Olivia Fuchs O, Nina F Gnädig NF, Greg Goldgof G, Maria Linares M, Maria G Gomez-Lorenzo MG, Cristina De Cózar C, Maria Jose Lafuente-Monasterio MJ, Sara Prats S, Stephan Meister S, Olga Tanaseichuk O, Melanie Wree M, Yingyao Zhou Y, Paul A Willis PA, Francisco-Javier Gamo FJ, Daniel E Goldberg DE, David A Fidock DA, Dyann F Wirth DF, Elizabeth A Winzeler EA
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.