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Science. 2018 Jan 12;359(6372):191-199. doi: 10.1126/science.aan4472.

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics.

Author information

1
School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
2
Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
4
Infectious Disease Program, The Broad Institute, 415 Main Street, Cambridge, MA 02142, USA.
5
Tres Cantos Medicines Development Campus, Malaria Discovery Performance Unit, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
6
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
7
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
8
Malaria Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
9
Medicines for Malaria Venture, Post Office Box 1826, 20 Route de Pre-Bois, 1215 Geneva 15, Switzerland.
10
Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, 9500 Gilman Drive, La Jolla, CA 92093, USA.
11
Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA.
12
Division of Infectious Diseases, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
13
School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA. ewinzeler@ucsd.edu.

Abstract

Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target-inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.

PMID:
29326268
PMCID:
PMC5925756
DOI:
10.1126/science.aan4472
[Indexed for MEDLINE]
Free PMC Article

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