Chemical genomic profiling for antimalarial therapies, response signatures, and molecular targets

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIAID	VIROL/MICRO-25

Authors

• J Yuan
• KC Cheng
• RL Johnson
• R Huang
• S Pattaradilokrat
• A Liu
• R Guha
• D Fidock
• J Inglese
• TE Wellems
• CP Austin
• XZ Su

Abstract

Malaria remains a devastating disease largely because of widespread drug resistance. New drugs and a better understanding of the mechanisms of drug action and resistance are essential for fulfilling the promise of eradicating malaria. Using high-throughput chemical screening and genome-wide association analysis, we identified 34 highly active compounds and genetic loci and genes associated with differential chemical phenotypes (DCPs), defined as five-fold differences in half-maximum inhibitor concentration (IC50) between parasite lines. Chromosomal loci associated with 49 DCPs were confirmed by linkage analysis and tests of genetically modified parasites, including three genes that were linked to 96% of the DCPs. Drugs with responses that mapped to wild type or mutant pfcrt alleles were tested in combination in vitro and in vivo, yielding promising new leads for antimalarial treatments.

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