TABLE 2

In vitro resistance mechanism of KAF156a

Selection agentCultureSNP(s)bMean IC50 (nM) ± SD
GNF707GNF452KAF156
DMSONone (Dd2, WT)8.1 ± 0.97.6 ± 2.01.8 ± 0.6
GNF7071RV1254F170492.0
2RL830V150612.0
3RE834D1,30036036
GNF4521RM1069I, L830V3,6001,20097
3RS1076I, L830V2,6007,3003,600
KAF1561ARQ821H, S1076R5,3001,90010
1BRP822T, S1076R>10,000>10,00073
2BRS1076I3,000>10,0001,600
3ARE834D6,9001,80024
3BRE834D5,0001,60016
  • a Five independent cultures of P. falciparum strain Dd2 were cultured in the presence of increasing concentrations of KAF156 over 4 months and, in a similar manner, three independent cultures were pressured with GNF707, and two independent cultures were pressured with GNF452. Parasitemia was monitored daily, and the compound concentration was increased 2-fold when the parasitemia reached ≥3%. For each of the resistant strains, the SNPs detected and the antimalarial activities (IC50) are as indicated for KAF156, GNF707, and GNF452. Data are presented to two significant figures as the median value from two to four independent experiments; the IC50s were consistent within 1.5-fold across experiments.

  • b SNPs, single-nucleotide polymorphisms. SNPs were confirmed by capillary sequencing of pfcarl (PFC0970w).