A broad analysis of resistance development in the malaria parasite.
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.
Department of Pediatrics, School of Medicine, University of California San Diego, 9500 Gilman Drive 0741, La Jolla, California 92093, USA.
Victoria C
VC
Corey
Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.|Infectious Disease Program, The Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Amanda K
AK
Lukens
Department of Medicine and Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Eva S
ES
Istvan
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Marcus C S
MCS
Lee
Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
Virginia
V
Franco
Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.
Pamela
P
Magistrado
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Olivia
O
Coburn-Flynn
Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.
Tomoyo
T
Sakata-Kato
Department of Pediatrics, School of Medicine, University of California San Diego, 9500 Gilman Drive 0741, La Jolla, California 92093, USA.
Olivia
O
Fuchs
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Nina F
NF
Gnädig
Department of Pediatrics, School of Medicine, University of California San Diego, 9500 Gilman Drive 0741, La Jolla, California 92093, USA.
Greg
G
Goldgof
Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
Maria
M
Linares
Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
Maria G
MG
Gomez-Lorenzo
Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
Cristina
C
De Cózar
Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
Maria Jose
MJ
Lafuente-Monasterio
Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
Sara
S
Prats
Department of Pediatrics, School of Medicine, University of California San Diego, 9500 Gilman Drive 0741, La Jolla, California 92093, USA.
Stephan
http://orcid.org/0000-0003-2436-7037
S
Meister
The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, California 92121, USA.
Olga
O
Tanaseichuk
Department of Pediatrics, School of Medicine, University of California San Diego, 9500 Gilman Drive 0741, La Jolla, California 92093, USA.
Melanie
M
Wree
The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, California 92121, USA.
Yingyao
Y
Zhou
Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.
Paul A
PA
Willis
Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
Francisco-Javier
FJ
Gamo
Department of Medicine and Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Daniel E
DE
Goldberg
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
David A
DA
Fidock
Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.|Infectious Disease Program, The Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Dyann F
DF
Wirth
Department of Pediatrics, School of Medicine, University of California San Diego, 9500 Gilman Drive 0741, La Jolla, California 92093, USA.
Elizabeth A
EA
Winzeler
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D002999:Clone Cells; D004351:Drug Resistance / Q000187:drug effects; D054643:INDEL Mutation / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010271:Parasites / Q000187:drug effects / Q000502:physiology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D000962:Antimalarials