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 - http://www.scopus.com/inward/record.url?scp=84975055690&partnerID=8YFLogxK
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 -
