Pharmacodynamic evaluation of BRII-693, a next-generation synthetic macrocyclic peptide antibiotic, in the neutropenic mouse thigh and lung infection models against gram-negative pathogens

BRII-693 is a next-generation synthetic macrocyclic peptide antibiotic for infections caused by drug-resistant gram-negative pathogens. This study evaluated the pharmacodynamic activity of BRII-693 against common gram-negative pathogens using neutropenic mouse thigh (11 strains) and lung (15 strains) infection models. BRII-693 exhibited dose-dependent increases in pharmacokinetic exposure in both plasma and epithelial lining fluid (ELF). Due to its prolonged elimination half-life within ELF, the ELF area under the curve (AUC) was higher than plasma AUC on a mg/kg basis. In dose-ranging PK/PD studies, BRII-693 demonstrated dose-dependent antibacterial activity. In both the thigh and lung models, bacterial stasis was achieved at 24 h plasma AUC/MIC values of 1-19 for <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, and <i>Acinetobacter baumannii</i>, and 1-log kill required only modestly higher targets given the steep exposure-response relationships. Higher target exposures were noted for <i>Pseudomonas aeruginosa</i> studies. In the lung model, BRII-693 achieved robust cidal endpoints against all tested organisms. Maximal effect (3-4 log reduction in bacterial burden) converged at a 24 h plasma AUC/MIC value of 50. These findings demonstrate robust PK/PD profile and <i>in vivo</i> efficacy of BRII-693 against clinically relevant gram-negative pathogens, supporting its potential as a next-generation macrocyclic peptide antibiotic.