Send to

Choose Destination
Nat Commun. 2016 Jun 15;7:11901. doi: 10.1038/ncomms11901.

A broad analysis of resistance development in the malaria parasite.

Author information

Department of Pediatrics, School of Medicine, University of California San Diego, 9500 Gilman Drive 0741, La Jolla, California 92093, USA.
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.
Department of Medicine and Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, California 92121, USA.
Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center