Table 1. Effects of the identified MMV Pathogen Box compounds on T. gondii proliferation.
Determination of the inhibitory properties of the identified compounds on the proliferation of (A) human foreskin fibroblast (HFF) cells or (B) T. gondii parasites, including wild type (WT) RH, WT ME49, atovaquone-resistant (ATVR) ME49, and ELQ-300-resistant (ELQR) RH and the corresponding ELQ sensitive (ELQS) parental strains. Data are reported as average EC50 (nM) ± SEM from three or more independent experiments. The selectivity index (SI) was calculated by dividing the EC50 against HFF cells by the EC50 against WT RH T. gondii parasites, with SI values >1 indicating increased selectivity towards the parasite. The fold change (FC) was calculated by dividing the EC50 against ATVR or ELQR parasites by the EC50 against WT ME49 or ELQS parasites respectively, with FC values >1 indicating increased resistance and FC values <1 indicating increased sensitivity to the tested compounds in the ATVR or ELQR strains. Paired t-tests were performed to compare the EC50 of the compounds in WT vs ATVR or ELQS vs ELQR parasites, and p-values are depicted as ns = not significant (p > 0.05), * p < 0.05, ** p < 0.01. ND = not determined.
| (A) Human | (B) T. gondii | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| HFF cells | WT RH | WT ME49 | ATVR ME49 | ELQS RH | ELQR RH | ||||
| Compound | EC50 (nM) | SI | EC50 (nM) | EC50 (nM) | EC50 (nM) | FC | EC50 (nM) | EC50 (nM) | FC |
| Atovaquone | >10,000 | >961 | 10.4 ± 0.5 | 14 ± 4 | 284 ± 34 | 20 * | 17 ± 2 | 3.5 ± 1.2 | 0.2 ** |
| Buparvaquone | >10,000 | >14,000 | 0.7 ± 0.1 | 0.7 ± 0.2 | 163 ± 14 | 233 ** | 1.3 ± 0.4 | 0.4 ± 0.03 | 0.3 ns |
| MMV671636 | ND | ND | 3.0 ± 0.2 | ND | ND | ND | ND | ND | ND |
| Auranofin | 2,793 ± 914 | 27 | 102 ± 27 | 92 ± 13 | 191 ± 44 | 2 ns | 364 ± 119 | 299 ± 42 | 0.8 ns |
| Trifloxystrobin | >10,000 | >357 | 28 ± 2 | 67 ± 18 | 24 ± 5 | 0.4 ns | 134 ± 4 | 39 ± 5 | 0.3 ** |
| Azoxystrobin | >10,000 | >32 | 310 ± 32 | 579 ± 48 | 232 ± 36 | 0.4 * | 659 ± 58 | 291 ± 4 | 0.4 * |
| MMV024397 | >10,000 | >42 | 238 ± 30 | 153 ± 18 | 441 ± 92 | 2.9 ns | 259 ± 40 | 121 ± 20 | 0.5 * |
| MMV688853 | >10,000 | >145 | 69 ± 12 | 178 ± 14 | 133 ± 4 | 0.7 ns | 151 ± 13 | 290 ± 12 | 1.9 * |
| ELQ-300 | ND | ND | ND | ND | ND | ND | 39 ± 4 | 263 ± 28 | 6.7 * |
| Antimycin A | ND | ND | ND | ND | ND | ND | 77 ± 9 | 454 ± 86 | 5.9 ns |