TABLE 1.
Drug susceptibility of the parental P. knowlesi (A1-H.1 clone) and orthologue replacement lines to ATP4 inhibitors (cipargamin, PA21A092, and SJ733) and control drugs (chloroquine and dihydroartemisinin)a
| Parasite line | EC50, nM (P value) |
||||
|---|---|---|---|---|---|
| Cipargamin | PA21A092 | SJ733 | Chloroquine | Dihydroartemisinin | |
| Parental | 9.51 ± 1.9 (0.5878) | 78.8 ± 13.6 (0.7185) | 375 ± 44 (0.2104) | 34.6 ± 4.3 (0.9899) | 1.43 ± 0.22 (0.9238) |
| PkATP4ORb | 13.5 ± 2.4 (NA)b | 126 ± 5.5 (NA) | 565 ± 48 (NA) | 39.0 ± 5.5 (NA) | 1.77 ± 0.25 (NA) |
| PfATP4OR | 1.62 ± 0.37 (0.0019) | 17.8 ± 2.9 (0.0317) | 71 ± 11 (<0.0001) | 34.6 ± 10.8 (0.9924) | 1.81 ± 0.29 (0.9999) |
| PmATP4OR | 9.44 ± 2.0 (0.5698) | 92.8 ± 14.7 (0.9072) | 238 ± 47 (0.0069) | 31.2 ± 4.1 (0.8382) | 1.75 ± 0.31 (0.9999) |
| PocATP4OR | 34.1 ± 1.6 (<0.0001) | 599 ± 70 (<0.0001) | 1057 ± 107 (0.0001) | 29.5 ± 7.0 (0.8222) | 1.73 ± 0.25 (0.9999) |
| PvATP4OR | 22.9 ± 4.2 (0.0172) | 94.8 ± 14.6 (0.9433) | 544 ± 140 (0.9997) | 33.7 ± 3.6 (0.9845) | 1.39 ± 0.24 (0.8725) |
| PkA1-H1c | 6.1 ± 0.5 (0.0647) | 63.8 ± 7.6 (0.3618) | 386 ± 34 (0.2222) | 29.3 ± 4.7 (0.6665) | 2.03 ± 0.25 (0.9824) |
| Pf3D7c | 0.89 ± 0.08 (0.0006) | 10.2 ± 1.4 (0.0139) | 64.3 ± 4.3 (<0.0001) | 15.9 ± 3.0 (0.0222) | 4.16 ± 0.52 (<0.0001) |
a
Parasites were exposed to drugs for one complete in vitro life cycle (27 h), and viability was measured using the SYBR green I method. Drug assays were run in technical duplicates on at least three biological replicates (up to eight times). Values are the mean ± SEM. P values were determined from post hoc analysis comparing EC50 data from all species to PkATP4OR data using Dunnett’s test.
b
NA, not applicable (as this is the comparator line).