Pharmacokinetics and In vivo Efficacy of Epetraborole against Burkholderia pseudomallei

Abstract

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 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 AUC-2 [~]110 {micro}g{middle dot}h/mL) produced >1.6 log CFU decreases from the start-of-therapy baseline across all ten B. pseudomallei strains. Notably, an AUC-2 of [~]110 {micro}g{middle dot}h/mL was achieved in humans with a 2000 mg IV dose in a phase 1 clincial 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 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 {beta}-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 EBOs robust and strain-independent therapeutic potential. Author SummaryMelioidosis is a life-threatening disease caused by Burkholderia pseudomallei, a bacterium found in soil and water in tropical regions. It is challenging to treat because it is often resistant to standard antibiotics, requires long courses of therapy, and can relapse even after treatment. New treatment options are urgently needed. Epetraborole is an experimental antibiotic with a novel mechanism that blocks bacterial protein synthesis. In this study, we tested how well epetraborole works in mice infected with B. pseudomallei, using ten different strains of the bacteria collected from geographically diverse regions. This is the first study to test a melioidosis treatment against such a broad panel of B. pseudomallei strains in an animal model. We found that epetraborole significantly reduced bacterial counts in the lungs of infected mice. The antibiotic remained effective even against strains with higher resistance and high bacterial loads 24 hours after infection, showing promise for severe clinical infections. Our findings suggest that epetraborole could be a valuable addition to existing melioidosis treatments, especially in regions with limited therapeutic options.