A broad analysis of resistance development in the malaria parasite

Victoria C. Corey, Amanda K. Lukens, Eva S. Istvan, Marcus C. S. Lee, Virginia Franco, Pamela Magistrado, Olivia Coburn-Flynn, Tomoyo Sakata-Kato, Olivia Fuchs, Nina F. Gnädig, Greg Goldgof, Maria Linares, Maria G. Gomez-Lorenzo, Cristina De Cózar, Maria Jose Lafuente-Monasterio, Sara Prats, Stephan Meister, Olga Tanaseichuk, Melanie Wree, Yingyao Zhou, Paul A. Willis, Francisco-Javier Gamo, Daniel E. Goldberg, David A. Fidock, Dyann F. Wirth and Elizabeth A. Winzeler ()
Additional contact information
Victoria C. Corey: School of Medicine, University of California San Diego
Amanda K. Lukens: Harvard T.H. Chan School of Public Health
Eva S. Istvan: Washington University School of Medicine
Marcus C. S. Lee: Columbia University College of Physicians and Surgeons
Virginia Franco: Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline
Pamela Magistrado: Harvard T.H. Chan School of Public Health
Olivia Coburn-Flynn: Columbia University College of Physicians and Surgeons
Tomoyo Sakata-Kato: Harvard T.H. Chan School of Public Health
Olivia Fuchs: School of Medicine, University of California San Diego
Nina F. Gnädig: Columbia University College of Physicians and Surgeons
Greg Goldgof: School of Medicine, University of California San Diego
Maria Linares: Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline
Maria G. Gomez-Lorenzo: Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline
Cristina De Cózar: Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline
Maria Jose Lafuente-Monasterio: Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline
Sara Prats: Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline
Stephan Meister: School of Medicine, University of California San Diego
Olga Tanaseichuk: The Genomics Institute of the Novartis Research Foundation
Melanie Wree: School of Medicine, University of California San Diego
Yingyao Zhou: The Genomics Institute of the Novartis Research Foundation
Paul A. Willis: Medicines for Malaria Venture
Francisco-Javier Gamo: Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline
Daniel E. Goldberg: Washington University School of Medicine
David A. Fidock: Columbia University College of Physicians and Surgeons
Dyann F. Wirth: Harvard T.H. Chan School of Public Health
Elizabeth A. Winzeler: School of Medicine, University of California San Diego

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11901

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