Genetic Mapping of Targets Mediating Differential Chemical Phenotypes in Plasmodium Falciparum

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2009 Sep 8

PMID 19734910

Citations 42

Authors

Jing Yuan

Ronald L Johnson

Ruili Huang

Jennifer Wichterman

Hongying Jiang

Karen Hayton

David A Fidock

Thomas E Wellems

James Inglese

Christopher P Austin

Xin-Zhuan Su

Affiliations

Soon will be listed here.

Abstract

Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits.

Citing Articles

Unravelling the mode of action of the Tres Cantos Antimalarial Set (TCAMS): investigating the mechanism of potent antimalarial compounds potentially targeting the human serotonin receptor.

Dos Santos B, Mallaupoma L, Pecenin M, Mohanty A, Lu A, Bartlett P Malar J. 2025; 24(1):45.

PMID: 39953553 PMC: 11827156. DOI: 10.1186/s12936-025-05271-3.

Hormones in malaria infection: influence on disease severity, host physiology, and therapeutic opportunities.

Das A, Suar M, Reddy K Biosci Rep. 2024; 44(11).

PMID: 39492784 PMC: 11581842. DOI: 10.1042/BSR20240482.

High Throughput Repurposing Screen Reveals Compounds with Activity Against Bradyzoites.

Uddin T, Xia J, Fu Y, McNamara C, Chatterjee A, Sibley L bioRxiv. 2024; .

PMID: 39005312 PMC: 11244992. DOI: 10.1101/2024.07.01.601569.

A Plasmodium falciparum RING Finger E3 Ubiquitin Ligase Modifies the Roles of PfMDR1 and PfCRT in Parasite Drug Responses.

Singh B, Zhang C, Wu J, Peng Y, He X, Tumas K Antimicrob Agents Chemother. 2023; 67(2):e0082122.

PMID: 36625569 PMC: 9933707. DOI: 10.1128/aac.00821-22.

Antiplasmodial Cyclodecapeptides from Tyrothricin Share a Target with Chloroquine.

Leussa A, Rautenbach M Antibiotics (Basel). 2022; 11(6).

PMID: 35740207 PMC: 9219824. DOI: 10.3390/antibiotics11060801.

References

Wu Y, Kirkman L, Wellems T . Transformation of Plasmodium falciparum malaria parasites by homologous integration of plasmids that confer resistance to pyrimethamine. Proc Natl Acad Sci U S A. 1996; 93(3):1130-4. PMC: 40043. DOI: 10.1073/pnas.93.3.1130. View

Su X, Hayton K, Wellems T . Genetic linkage and association analyses for trait mapping in Plasmodium falciparum. Nat Rev Genet. 2007; 8(7):497-506. DOI: 10.1038/nrg2126. View

Inglese J, Auld D, Jadhav A, Johnson R, Simeonov A, Yasgar A . Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci U S A. 2006; 103(31):11473-8. PMC: 1518803. DOI: 10.1073/pnas.0604348103. View

Mu J, Awadalla P, Duan J, McGee K, Keebler J, Seydel K . Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome. Nat Genet. 2006; 39(1):126-30. DOI: 10.1038/ng1924. View

Weisman J, Liou A, Shelat A, Cohen F, Guy R, DeRisi J . Searching for new antimalarial therapeutics amongst known drugs. Chem Biol Drug Des. 2006; 67(6):409-16. PMC: 1592519. DOI: 10.1111/j.1747-0285.2006.00391.x. View

Su X, Wootton J . Genetic mapping in the human malaria parasite Plasmodium falciparum. Mol Microbiol. 2004; 53(6):1573-82. DOI: 10.1111/j.1365-2958.2004.04270.x. View

Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, Vanichtanankul J, Sirawaraporn W, Taylor P . Insights into antifolate resistance from malarial DHFR-TS structures. Nat Struct Biol. 2003; 10(5):357-65. DOI: 10.1038/nsb921. View

Mu J, Ferdig M, Feng X, Joy D, Duan J, Furuya T . Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Mol Microbiol. 2003; 49(4):977-89. DOI: 10.1046/j.1365-2958.2003.03627.x. View

Montalar M, Nalda-Molina R, Rodriguez-Ibanez M, Garcia-Valcarcel I, Garrigues T, Merino V . Kinetic modeling of triamterene intestinal absorption and its inhibition by folic acid and methotrexate. J Drug Target. 2003; 11(4):215-23. DOI: 10.1080/10611860310001615947. View

10.

Chong C, Chen X, Shi L, Liu J, Sullivan Jr D . A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol. 2006; 2(8):415-6. DOI: 10.1038/nchembio806. View

11.

Hayton K, Su X . Genetic and biochemical aspects of drug resistance in malaria parasites. Curr Drug Targets Infect Disord. 2004; 4(1):1-10. DOI: 10.2174/1568005043480925. View

12.

Noedl H, Se Y, Schaecher K, Smith B, Socheat D, Fukuda M . Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008; 359(24):2619-20. DOI: 10.1056/NEJMc0805011. View

13.

Liu S, Mu J, Jiang H, Su X . Effects of Plasmodium falciparum mixed infections on in vitro antimalarial drug tests and genotyping. Am J Trop Med Hyg. 2008; 79(2):178-84. PMC: 2680026. View

14.

Broman K, Wu H, Sen S, Churchill G . R/qtl: QTL mapping in experimental crosses. Bioinformatics. 2003; 19(7):889-90. DOI: 10.1093/bioinformatics/btg112. View

15.

Hayton K, Gaur D, Liu A, Takahashi J, Henschen B, Singh S . Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of Plasmodium falciparum invasion. Cell Host Microbe. 2008; 4(1):40-51. PMC: 2677973. DOI: 10.1016/j.chom.2008.06.001. View

16.

Baniecki M, Wirth D, Clardy J . High-throughput Plasmodium falciparum growth assay for malaria drug discovery. Antimicrob Agents Chemother. 2006; 51(2):716-23. PMC: 1797774. DOI: 10.1128/AAC.01144-06. View

17.

Price R, Uhlemann A, Brockman A, McGready R, Ashley E, Phaipun L . Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004; 364(9432):438-447. PMC: 4337987. DOI: 10.1016/S0140-6736(04)16767-6. View

18.

Schaerlinger B, Hickel P, Etienne N, Guesnier L, Maroteaux L . Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy. Br J Pharmacol. 2003; 140(2):277-84. PMC: 1574033. DOI: 10.1038/sj.bjp.0705437. View

19.

Gardner M, Hall N, Fung E, White O, Berriman M, Hyman R . Genome sequence of the human malaria parasite Plasmodium falciparum. Nature. 2002; 419(6906):498-511. PMC: 3836256. DOI: 10.1038/nature01097. View

20.

Kublin J, Dzinjalamala F, Kamwendo D, Malkin E, Cortese J, Martino L . Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis. 2002; 185(3):380-8. DOI: 10.1086/338566. View