Preclinical evaluation of epetraborole in the hollow fibre system model of Mycobacterium abscessus lung disease.

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.