A broad analysis of resistance development in the malaria parasite

TY - JOUR

T1 - A broad analysis of resistance development in the malaria parasite

AU - Corey, Victoria C.

AU - Lukens, Amanda K.

AU - Istvan, Eva S.

AU - Lee, Marcus C.S.

AU - Franco, Virginia

AU - Magistrado, Pamela

AU - Coburn-Flynn, Olivia

AU - Sakata-Kato, Tomoyo

AU - Fuchs, Olivia

AU - Gnädig, Nina F.

AU - Goldgof, Greg

AU - Linares, Maria

AU - Gomez-Lorenzo, Maria G.

AU - De Cózar, Cristina

AU - Lafuente-Monasterio, Maria Jose

AU - Prats, Sara

AU - Meister, Stephan

AU - Tanaseichuk, Olga

AU - Wree, Melanie

AU - Zhou, Yingyao

AU - Willis, Paul A.

AU - Gamo, Francisco-Javier

AU - Goldberg, Daniel E.

AU - Fidock, David A.

AU - Wirth, Dyann F.

AU - Winzeler, Elizabeth A.

N1 - Funding Information: This work was supported by grants from the Bill and Melinda Gates Foundation (OPP1040406) and the National Institute of Allergy and Infectious Diseases (R01AI103058). Victoria Corey received support from a UCSD Genetics Training Program through an institutional training grant from the National Institute of General Medical Sciences (T32 GM008666).

PY - 2016/6/15

Y1 - 2016/6/15

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84975055690

U2 - 10.1038/ncomms11901

DO - 10.1038/ncomms11901

M3 - Article

C2 - 27301419

AN - SCOPUS:84975055690

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11901

ER -