Gregory Goldgof, Elizabeth Winzeler and colleagues from the University of California, San Diego in the U.S. have developed a drug-sensitive yeast strain by deleting the main multi-drug export pumps to help identify the mechanisms of action of the 400 next-generation anti-malarial drug candidates in the Malaria Box. This will help optimize drug safety and efficacy for clinical trials. In Phase I, they successfully screened the Malaria Box compounds and identified 30 that were active in their assay. They also performed directed evolution studies by exposing the yeast to increasing sublethal concentrations of 21 of the active compounds. Resistant yeast clones were then sequenced to identify the likely molecular targets. In Phase II, they will exploit the same yeast strain to identify targets for compounds with activity specifically against either the liver stage of the malaria parasite, which could be used to cure infected patients, or the gametocyte stage, which could reduce the rate of malaria transmission. Their approach is particularly valuable for these types of compounds as they cannot be used for directed evolution studies in the malaria parasites themselves.