Pharmacokinetics and in vivo efficacy of epetraborole against Burkholderia pseudomallei

Melioidosis, caused by Burkholderia pseudomallei, remains a major therapeutic challenge due to high relapse rates and intrinsic antibiotic resistance. Epetraborole (EBO), a leucyl-tRNA synthetase inhibitor, represents a novel therapeutic approach with a distinct mechanism of action compared to standard-of-care antibiotics. Preclinical studies included minimum inhibitory concentration (MIC) determination, pharmacokinetic (PK) profiling, dose range and fractionation studies, and efficacy assessments in a 24-hour post-bacterial challenge model of a murine B. pseudomallei lung infection. EBO demonstrated a clear dose-dependent reduction in lung bacterial burden. Doses ≥ 200 mg/kg (achieving area under the curve (AUC)_0-24 ~110 µg·h/mL) produced > 1.6 log₁₀ CFU decreases from the start-of-therapy baseline across all ten B. pseudomallei strains. Notably, an AUC_0-24 of ~ 110 µg·h/mL was achieved in humans with a 2000 mg IV dose in a phase 1 clinical trial where doses up to 4000 mg per day for 14 days were well tolerated with no serious adverse events or dose-limiting adverse events. When EBO doses of 600, 300 and 100 mg/kg delivered subcutaneously (SC) were fractionated by once, twice and three times a day against the B. pseudomallei strain NCTC7383, which represents the MIC₁₀₀ strain, the efficacy indicated that the pharmacokinetics-pharmacodynamics (PK/PD) driver of epetraborole is total drug exposure (AUC) rather than peak concentration (Cmax) or time above MIC. The inhibition of leucyl-tRNA synthetase represents a unique molecular target, reducing cross-resistance potential with existing β-lactam antibiotics and enabling combination therapy strategies. These findings substantiate EBO as a promising therapeutic option for clinical melioidosis to improve treatment outcomes. Notably, this study represents the first demonstration of in vivo efficacy against a panel of ten genetically and geographically diverse B. pseudomallei strains in a murine model. This unprecedented breadth of strain coverage provides strong evidence of EBO's robust and strain-independent therapeutic potential.