Preclinical evaluation of epetraborole in the hollow fibre system model of Mycobacterium abscessus lung disease
Year: 2025
Type: article
Abstract: BACKGROUND: In patients with Mycobacterium abscessus (MAB) lung disease (LD), guideline-based therapy (GBT) achieves sputum culture conversion in only 20-35% of patients. The poor efficacy is reflected in the hollow fibre model system for MAB-LD (HFS-MAB), where GBT drugs' maximal microbial kill (Emax) below day 0 burden (B0) were amikacin 3 colony-forming units (cfu)/mL, clarithromycin-cefoxitin-amikacin (GBT) 17 cfu/mL, imipenem 20 cfu/mL, and tigecycline 24 cfu/mL. METHODS: We tested the bacterial leucyl-tRNA synthetase (LeuRS) inhibitor, epetraborole, for MICs in 59 MAB isolates, and with seven epetraborole exposures in the HFS-MAB over 21 days. Data were analysed using the inhibitory sigmoid Emax model for microbial kill, and a quadratic function for resistance. Monte Carlo experiments (MCE) were performed to identify the optimal epetraborole dose for the clinic. RESULTS: The epetraborole MIC50 was 0.125 mg/L, and the MIC90 was 0.25 mg/L. Epetraborole killed 253 cfu/mL below B0. However, epetraborole microbial effect was terminated by antimicrobial resistance, in an exposure-dependent fashion. Whole genome sequencing revealed concentration-dependent generation of resistance-associated LeuRS mutations, including novel mutations such as Asp433Val, Arg324Ser, and Phe310Cys. The exposure mediating 80% of Emax (EC80) was an AUC0-24/MIC = 202.73. In MCE 750 mg twice daily achieved EC80 in 95.6% and 79.2% of virtual patients for intravenous versus oral administration, respectively. CONCLUSION: Epetraborole microbial kill is the best, thus far, achieved in the HFS-MAB, more than two times omadacycline's 123 cfu/mL below B0. We propose to test a novel combination regimen of epetraborole plus omadacycline plus a β-lactam versus GBT first in the HFS-MAB, followed by clinical trials.
DOI: 10.1093/jac/dkaf405
Institutions: The University of Texas at Tyler, University of California Davis Medical Center, UC Davis Health, University of California, Davis, National Jewish Health, University of Colorado Anschutz, University of Colorado Denver, Xiamen Innovax Biotech Co., Ltd. (China), The University of Texas Health Science Center at Tyler
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4415938646