Figure 2: Mutations in ScPMA1 confer resistance to KAE609, sensitize yeast to edelfosine, and treatment with KAE609 leads to a change in cytosolic pH. | Scientific Reports

Figure 2: Mutations in ScPMA1 confer resistance to KAE609, sensitize yeast to edelfosine, and treatment with KAE609 leads to a change in cytosolic pH.

From: Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor

Figure 2

(a) Changes in ABC16-Monster KAE609 resistance associated with mutations introduced using the CRISPR/Cas9 system, relative to the unmodified parent line. (b) The CRISPR mutant containing the ScPma1p:L290S amino acid change was tested for cross resistance or sensitivity to a range of antimicrobials. It shows 7.5-fold cross sensitivity to edelfosine, a chemical known to indirectly inhibit ScPma1p function. (c) The effect of KAE609 treatment on cytosolic pH was measured using cytosolically expressed ratiometric pHluorin, a pH-sensitive GFP19. Cytosolic pH was measured for three biological replicates. pH values are represented as mean ± standard deviations. P values for IC50 fold-changes were determined using a one-tailed ratio paired t-test comparing the ratio of the mutant-strain IC50 value to that of the parental strain. For all bar graphs, (*) indicates p < 0.05 and (**) indicates p < 0.01).

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