Drug resistance is the major obstacle to control of malaria and the spread of resistance has increased malaria mortality over recent decades. Identification of parasite genes that influence drug response would improve our ability to monitor resistance spread, provide tools for better understanding the mode of action of antimalarials, and allow rational redesign of existing drugs. In Thailand the problem is particularly severe with high levels of resistance to all classes of antimalarials except for the artemisinin derivatives. In the initial funding period of this project we measured response to eight drugs in 825 parasite isolates from a single clinic on the Thailand-Burma border, and then genotyped 323 single-clone parasites using 426 di-nucleotide microsatellite markers spaced at 50kb (~3cM) intervals throughout the genome. This work resulted in identification of a number of candidate regions that show association with response to one or more drugs. This renewal application capitalizes on these findings. We propose to (1) identify candidate genes and alleles that influence drug response using comparative sequencing and fine-scale association mapping, (2) use rapid transfection approaches to confirm which of the candidate genes identified are involved in resistance, and (3) examine whether specific alleles in these genes can predict drug treatment failure using clinical samples collected from patients in Thailand. Relevance of this research to public health. Malaria kills over one million people each year. The mainstay of malaria control is drug treatment, but treatment options are rapidly running out due to the evolution of resistance.
We aim to locate parasite genes underlying resistance. This will allow us to track the spread of resistance, to better understand how antimalarial drugs work, and to redesign drugs to restore their effectiveness.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DDR (01))
Program Officer
Joy, Deirdre A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Texas Biomedical Research Institute
San Antonio
United States
Zip Code
Echeverry, Diego F; Nair, Shalini; Osorio, Lyda et al. (2013) Long term persistence of clonal malaria parasite Plasmodium falciparum lineages in the Colombian Pacific region. BMC Genet 14:2
Simpson, Julie A; Jamsen, Kris M; Anderson, Tim J C et al. (2013) Nonlinear mixed-effects modelling of in vitro drug susceptibility and molecular correlates of multidrug resistant Plasmodium falciparum. PLoS One 8:e69505
Phyo, Aung Pyae; Nkhoma, Standwell; Stepniewska, Kasia et al. (2012) Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet 379:1960-6
Nkhoma, Standwell C; Nair, Shalini; Cheeseman, Ian H et al. (2012) Close kinship within multiple-genotype malaria parasite infections. Proc Biol Sci 279:2589-98
Cheeseman, Ian H; Miller, Becky A; Nair, Shalini et al. (2012) A major genome region underlying artemisinin resistance in malaria. Science 336:79-82
Anderson, Tim; Nkhoma, Standwell; Ecker, Andrea et al. (2011) How can we identify parasite genes that underlie antimalarial drug resistance? Pharmacogenomics 12:59-85
Nair, Shalini; Nkhoma, Standwell; Nosten, Francois et al. (2010) Genetic changes during laboratory propagation: copy number At the reticulocyte-binding protein 1 locus of Plasmodium falciparum. Mol Biochem Parasitol 172:145-8
Anderson, Tim J C; Nair, Shalini; Nkhoma, Standwell et al. (2010) High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia. J Infect Dis 201:1326-30
Anderson, Tim J C; Williams, Jeff T; Nair, Shalini et al. (2010) Inferred relatedness and heritability in malaria parasites. Proc Biol Sci 277:2531-40
Anderson, Tim J C; Patel, Jigar; Ferdig, Michael T (2009) Gene copy number and malaria biology. Trends Parasitol 25:336-43

Showing the most recent 10 out of 29 publications