Fig. 4: Translation of JNJ-6640 activity.

a, Susceptibility of JNJ-6640 in a foamy macrophage assay. IC₅₀ comparison at day 4 (30 µM) and day 4 + 1 (0.66 µM); ratio of 45 (bactericidal). n = 2 individual experiments with 4 technical replicates. b, JNJ-6640 (1,500 mg kg⁻¹ LAI; subcutaneous) efficacy in an acute mouse model for TB administered once fortnightly (6640 1/14, 7 days post-infection and day 1 treatment phase) or once weekly (6640 2/14, 7 and 14 days post-infection, and day 1 and day 7 treatment phase). 21 Days post-infection data are shown. n = 5 animals. Representative of two independent experiments. BDQ, 25 mg kg⁻¹ bedaquiline oral administration (PO) once daily (qd). c, JNJ-6640 (1,500 mg kg⁻¹ LAI; subcutaneous) efficacy in the chronic mouse model for TB. 84 Days post-infection are shown. n = 6 animals. 6640 8/56, 8× doses, once weekly of JNJ-6640. d, In vitro combination studies replacing linezolid with JNJ-6640. Day 10 data are shown. 6640, 10 µM JNJ-6640; B, 0.5 µM bedaquiline; HR, 5.8 µM isoniazid and 14.58 µM rifampicin; L, 6 µM linezolid; Pa, 7 µM pretomanid. Bedaquiline, pretomanid and linezolid concentrations reflect the mouse equivalent human dose based on efficacious exposure. The full dataset is shown in Extended Data Fig. 9. n = 3 biological replicates, representative of two independent experiments. Dashed line indicates the starting inoculum. e, In vivo combination study demonstrating that JNJ-6640 can replace linezolid in a high acute model. Two week treatment. 24 Days post-infection are shown. 6,640, 1,500 mg kg⁻¹ JNJ-6640 LAI (subcutaneous; once weekly); B, 25 mg kg⁻¹ bedaquiline (PO qd); L, 100 mg kg⁻¹ linezolid (PO qd); Pa, 40 mg kg⁻¹ pretomanid (PO qd); SoT, start of treatment (10 days post-infection). n = 5 (SoT) or 6 (treatment groups) animals. For all panels, data shown are mean ± s.d. Significance was calculated with one-way analysis of variance (ANOVA) with Dunnett’s (b), Tukey’s multiple comparisons (d,e) or two-sided unpaired t-test (c).

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