Figure 1
Single agent and combination analysis of a large collection of approved and investigational drugs for antimalarial activity.
(A) Examples of response profiles (10 × 10 plots) for Artesunate (AS) + Mefloquine (MFQ). Percent response values represent normalized growth, relative to controls based on SybrGreen fluorescence intensities. (B) Interaction plot of combinations passing a defined threshold (DBSumNeg <−3; reflecting synergy) against the Plasmodium falciparum 3D7 strain (
 = Endoperoxides; 
 = HLF, LUM, MFQ, CQ, TFQ; 
 = hPI3K/mTOR; 
 = mitochondrial/DHODH; 
 = ion channel modulator; 
 = hybrid mechanism; 
 = other). Vector lengths do not reflect the strength or weakness of the interaction. Additional network plots reflecting antagonistic outcomes are found in the SI. Enlarged versions of this figure can be found online at http://tripod.nih.gov/pub/malaria-matrix/. (C) The interaction network formed from 2134 combinations of 111 single agents is colored grey. Overlaid on top (black edges) is the sub-network of 110 combinations involving all the single agents representing the most synergistic combinations (as measured by the sum of the DBSumNeg metric). (
 = antimalarial drugs; 
 = growth inhibitor; 
 = hPI3K/mTOR; 
 = mitochondrial/DHODH; 
 = ion channel modulator; 
 = signaling/transporter inhibitor. Large symbols correspond to the high potency class and small symbols correspond to medium potency class). (D) Hierarchical clustering of combination profiles based upon 1) synergy assessment; 2) potency class; 3) mechanism of action (MOA) relationship. The number of clusters (six) was selected based on the largest number of clusters that led to zero or one cluster that was not enriched in any MOA combination (at the 0.01 level). (E) A summary of MOA combinations enriched in cluster 3 (green), relative to the entire dataset (see SI for full list of code definitions). Enrichment was tested using Fisher’s exact test with p-values adjusted using the Benjamini-Hochberg method and plotted as –log10 p-value. The blue and red dashed lines correspond to p = 0.05 and p = 0.01 respectively. While six MOA combinations were significant at the 0.01 level, we annotated the top three. See SI for full figure.
