A, Plot of chemical clusters with common response signatures and the number of Plasmodium falciparum lines; B, clustering of parasites based on patterns of parasite responses (IC₅₀ values). Cam1, parasites from Cambodia; SA, South America; AF/Thai/CA, Africa, Thailand, and Central America; Thai/Cam2, Thailand and Cambodia; * indicates two parasites from Africa. C, principal component analysis (PCA) of parasite response patterns showing separation of parasite continental populations; D, correlation plot of the top compounds (eigenvector values <−0.14 or >0.14) positively and negatively contributing to PCA component 2 separating American population from Asian and African populations. E, correlation plot of the top compounds (eigenvector values <−0.14 or >0.14) positively and negatively contributing to PCA component 5 separating African and Southeast Asian populations. For the full names of the compounds, please see Table S6.

A, plots of quantitative trait loci from compounds with a LOD score >3.0 in the Dd2×HB3 cross; B, plot of quantitative trait loci from compounds with a LOD score >3.0 in the 7G8×GB4 cross.

For all sub-figures, CQ, chlorquine; Mib, mibefradil; NNC, NNC55-0396. A, positive and negative correlations of compounds mapped to pfcrt; the color bar indicates correlation coefficient values from 1(100% positive correlation, red) to −1 (100% negative correlation, blue). B, Ratios of IC₅₀ values from drug treatments with or without IC₁₅ level of CQ for the Dd2 line. Red and blue bars indicate ratios for compounds whose responses are negatively and positively correlated with CQ, respectively. * compounds with IC₅₀<100 nM in the presence of IC₁₅ levels of CQ. C, Isobolograms showing synergistic interactions of CQ with NNC (blue dots) or Mib (red dots) in the CQ-resistant Dd2, but slightly antagonistic in the CQ-sensitive HB3 parasite (red circles, Mib; blue circles, NNC); FIC IC₅₀, fractional inhibitory concentration. Shown are representative plots of two independent experiments for each combination. D and E, Mean parasitemia and standard deviations from groups of 3-6 mice treated with various doses of Mib (D) or NNC (E) in the presence (blue bars) or absence (red bars) of 3 mg/kg CQ. CQ3, 3 mg/kg CQ. The numbers after Mib (NNC) are Mib (NNC) doses in mg/kg, and the numbers after CM (CN) are Mib (NNC) doses plus 3 mg/kg CQ. F, Plots of mean growth inhibition with standard errors from D and E to estimate IC₅₀ values; blue lines, NNC; red lines, Mib; dash lines, without CQ; solid lines, with 3 mg/kg CQ.