Fig. 1. First-generation lead RO7075573 protects mice from A. baumannii infections.
a, The chemical structure of tethered macrocyclic peptides, from the screening hit RO7036668 to the first-generation lead RO7075573. RO7055137 is an inactive control compound (MIC > 64 mg l−1) (Fig. 3c). b,c, The in vivo efficacy of RO7075573 in a mouse model of infection induced by A. baumannii ACC00535 (RO7075573 MIC = 0.12 mg l−1 in CAMHB with 20% human serum). b, Sepsis was induced by intraperitoneal bacterial inoculation in immunocompetent mice. Doses (mg per kg) were administered subcutaneously at 1 and 5 h after infection. The Kaplan–Meier survival curve shows the percentage of mouse survival for each group treated with vehicle, meropenem (80 mg per kg) or varying doses of RO7075573 (n = 10 per group) over 6 days. c, Thigh infection was induced by bacterial intramuscular inoculation in immunocompromised mice. Starting 2 h after infection (0 h), mice were given s.c. administration of RO7075573 or meropenem (MEM) (n = 4 mice per treatment group or vehicle) every 4 h over 24 h. The dose–response curve of RO7075573 total daily doses (mg per kg per day) is shown, measured as the bacterial burden reduction (CFU) in infected thigh (8 thighs, 8 read-outs for bacterial counts). Results are presented as mean ± s.d. The statistical significance of the difference in bacterial counts between control and treated mice was calculated using one-factor analysis of variance (ANOVA) followed by Dunnett’s multiple-comparison test (P < 0.05 was considered to be significant versus T = 0 h); ****P < 0.0001.