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<p>Melioidosis, caused by <i>Burkholderia pseudomallei</i>, 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 <i>B. pseudomallei</i> lung infection. EBO demonstrated a clear dose-dependent reduction in lung bacterial burden. Doses ≥ 200&#xa0;mg/kg (achieving area under the curve (AUC)<sub>0–24</sub> ~110&#xa0;µg·h/mL) produced &gt; 1.6 log<sub>10</sub> CFU decreases from the start-of-therapy baseline across all ten <i>B. pseudomallei</i> strains. Notably, an AUC<sub>0–24</sub> of ~ 110&#xa0;µg·h/mL was achieved in humans with a 2000&#xa0;mg IV dose in a phase 1 clinical trial where doses up to 4000&#xa0;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&#xa0;mg/kg delivered subcutaneously (SC) were fractionated by once, twice and three times a day against the <i>B. pseudomallei</i> strain NCTC7383, which represents the MIC<sub>100</sub> 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 <i>B. pseudomallei</i> strains in a murine model. This unprecedented breadth of strain coverage provides strong evidence of EBO’s robust and strain-independent therapeutic potential.</p>

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Pharmacokinetics and in vivo efficacy of epetraborole against Burkholderia pseudomallei

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月22日

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  • Jason E. Cummings,
  • Danara Flores,
  • Vincent E. Guglielmi,
  • Gregory Dooley,
  • M. R. K. Alley,
  • Richard A. Slayden

摘要

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 AUC0–24 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.