Fig. 4.
MBX-4055 exhibits broad-spectrum activity and is refractory to acquired resistance. (A) Continuous recording of sorbitol-induced osmotic lysis without (black trace) or with 3.2, 16, 80, 400, 2000 nM MBX-4055. PSAC-mediated permeability is inversely proportional to the time to hemolysis. (B) Mean ± S.D. PSAC block K0.5 and parasite growth inhibition IC50 values for MBX-4055 against indicated P. falciparum lines [red (left) and black (right) bars, respectively; n = 3–4 dose response experiments each]. The inhibitor retains broad activity against these lines, which represent all malaria-endemic continents and the full range of antimalarial susceptibilities. (C) MBX-4055 growth inhibition dose responses for Dd2 and Dd24055 (black circles and red triangles), showing unchanged potency against in vitro parasite growth after 6 months of in vitro selection (P = 0.1, n = 3). (D) Mean ± S.D. sorbitol permeability (Ps) at indicated [MBX-4055] for the parental Dd2 and Dd24055 lines (black circles and red triangles), normalized to 1.0 without inhibitor. There was a statistically insignificant change in MBX-4055 potency against the target (P = 0.1, n = 3). (E) Unchanged sorbitol permeability in Dd24055 (P = 0.49, n = 3), excluding upregulation of target activity by selective pressure.