title: Chemical genomic profiling for antimalarial therapies, response signatures, and molecular targets.
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 32 highly active compounds and genetic loci associated with differential chemical phenotypes (DCPs), defined as greater than or equal to fivefold differences in half-maximum inhibitor concentration (IC(50)) 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 whose responses mapped to wild-type or mutant pfcrt alleles were tested in combination in vitro and in vivo, which yielded promising new leads for antimalarial treatments.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Ken Chih-Chien
authors.initials: KC
authors.lastname: Cheng
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Johnson
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Sittiporn
authors.initials: S
authors.lastname: Pattaradilokrat
authors.forename: Anna
authors.initials: A
authors.lastname: Liu
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Guha
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.forename: James
authors.initials: J
authors.lastname: Inglese
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wellems
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Xin-zhuan
authors.initials: XZ
authors.lastname: Su
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D005075:Biological Evolution; D002874:Chromosome Mapping; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D017125:Genes, Protozoan; D008040:Genetic Linkage; D056426:Genetic Loci; D018503:Genome, Protozoan; D055106:Genome-Wide Association Study; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D026901:Membrane Transport Proteins / Q000235:genetics; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum