Journal Article

A broad analysis of resistance development in the malaria parasite

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

2016

Overview

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. It is unclear whether new antimalarial compounds may rapidly lose effectiveness in the field because of parasite resistance. Here, Corey et al. investigate the acquisition of drug resistance and the extent to which common resistance mechanisms decrease susceptibility to a diverse set of 50 antimalarial compounds.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/34 / 14/63 / 631/250/255/1629 / 631/326/417/1716 / 631/92/436 / Alleles / Animals / Antimalarials - pharmacology / Chemotherapy / Clone Cells / Cross-resistance / Cytochrome bc1 / Cytochromes / Drug resistance / Drug Resistance - drug effects / Hsp90 protein / Humanities and Social Sciences / INDEL Mutation - genetics / Malaria / Microorganisms / multidisciplinary / Mutation - genetics / Parasite resistance / Parasites / Parasites - drug effects / Parasites - physiology / Plasmodium falciparum - drug effects / Plasmodium falciparum - physiology / Polymorphism, Single Nucleotide - genetics / Ribonucleic acid / RNA / Science / Science (multidisciplinary) / Vector-borne diseases