Table 2.
P. falciparum asexual blood-stage minimal inoculum for resistance (MIR) selection summary
Name | Chemical class | Starting selective pressure | Resistant parasites in 4 wells of 2.5 × 106 | Resistant parasites in 3 wells of 3 × 107 | Resistant parasites in 3 flasks of 3 × 108 | MIR | Selected proteasome mutation | IC50 fold shift against selection compound |
---|---|---|---|---|---|---|---|---|
WLL | vinyl sulfone | 3 × IC50 (50.4 nM) | none | none | none | >1 × 109 | N/A | N/A |
J-71 | epoxyketone | 3 × IC50 (152.4 nM) | none | 1/3 wells | N/D | 1 × 108 | β5 A50V | 3.1× |
J-80 | epoxyketone | 3 × IC50 (88.2 nM) | none | none | 3/3 flasks | 3 × 108 | β5 M45R, β5 M45V | 35.1×, 11.6× |
TDI-8304 | macrocyclic peptide | 3 × IC50 (33 nM) | none | 3/3 wells | N/D | 3 × 107 | β6 S157L, β6 N151Y | 2,621×, 1.7× |
IC50 fold shifts were calculated as the ratio of the IC50 of a compound against the selected mutant over its IC50 against the Dd2-B2 parental line. N, n = 3–20, 2. N/D, not done; N/A, not applicable. MIRs were calculated as the total number of parasites inoculated divided by the total number of positive cultures (when obtained). The formula extends up to the largest inoculum at which parasites were obtained (or tested in the case of negative cultures), and includes lower inocula (see STAR Methods).