Format

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

1
Department of Pediatrics, School of Medicine, University of California San Diego, 9500 Gilman Drive 0741, La Jolla, California 92093, USA.
2
Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.
3
Infectious Disease Program, The Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
4
Department of Medicine and Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
5
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
6
Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
7
The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, California 92121, USA.
8
Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.

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.

PMID:
27301419
PMCID:
PMC4912613
DOI:
10.1038/ncomms11901
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

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