Figure 2.

Binding at the P2 pocket is important for the efficacy of the new series of MptpB inhibitors. (a) Mode of binding of the representative compound 5 into the active site of MptpB, as suggested from the molecular docking. (b) Mutation of key interacting residues at the P2 pocket resulted in a loss of 2–5 fold the IC₅₀ values (μM). (c) Cell activity of the new series results in substantial (81–87%) reduction in the mycobacterial (BCG) burden of infected mouse macrophages (J774) 72 h post infection, compared to DMSO-treated macrophages. Reduction in bacterial burden is already observed at 24 h postinfection (Supporting Information Figure 2). Plots represent the average CFUs (+SEM) per well (from a 96-well plate, see Experimental Methods for details) of at least three independent experiments, with statistical significance relative to the control (DMSO treated) established using one-way ANOVA, Dunnett’s test (****p value < 0.0001, **p = 0.012). Inset shows viability of treated macrophages.