1713. In Vitro Activities of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor, Against Mycobacterium avium Complex Isolates

Abstract

Abstract Background Epetraborole (EBO) is a boron-containing, oral inhibitor of bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis; EBO demonstrates potent activity against nontuberculous mycobacteria. We evaluated the effects of select culture conditions on MIC determinations of EBO against isolates of M. avium complex (MAC), as well as EBO MIC90 results with Middlebrook 7H9 broth compared to those with cation-adjusted Mueller Hinton Broth (CAMHB) for 51 MAC isolates. Methods Six strains of MAC were used to test the in vitro activity of EBO in different conditions in a broth microdilution (BMD) assay. Activity was compared in Middlebrook 7H9 and CAMHB with 5% OADC from different manufacturers. The effects of glycerol, cations, oxyrase, varying pH levels, and increasing inoculum sizes were tested. Finally, EBO in vitro activity was tested for 51 MAC isolates in a BMD assay in both Middlebrook 7H9 and CAMHB with 5% OADC. Results In general, manipulation of select culture conditions caused very little variation in EBO MIC values for the 6 MAC strains except for increasing the inoculum from ∼105 to 107 CFU/mL, which caused an approximately 64x increase in the MIC. Since 1 MAC isolate out of 6 was affected by the addition of casitone, we tested 51 MAC isolates in both the minimal media Middlebrook 7H9 and the complex media CAMHB. EBO had a narrow MIC range in both broths, 0.25-8 mg/L for all isolates. The EBO modal MIC, MIC50 and MIC90 for the entire MAC panel of 51 isolates was 2 mg/L, 2 mg/L, and 8 mg/L for CAMHB and 1 mg/L, 1 mg/L, and 4 mg/L for Middlebrook 7H9, respectively (Table 1). Three clarithromycin-resistant isolates had EBO MIC values of 0.5 mg/L, 1 mg/L, and 2 mg/L suggesting that clarithromycin resistance does not affect EBO in vitro activity. In addition, amikacin resistance as determined using the Clinical Laboratory Standards Institute (CLSI) IV amikacin breakpoint (MIC ≥ 64 mg/L) had no noticeable effect on EBO MIC values. Table 1EBO In Vitro Activity Against 51 Isolates of Mycobacterium avium complex Conclusion The MIC distribution for the 51 MAC isolates tested was similar in both media types, indicating that CAMHB can be used to test EBO MAC susceptibilities per CLSI guidelines. Clarithromycin- and amikacin-resistant isolates demonstrated no cross-resistance with EBO. Disclosures Michelle S. DeStefano, n/a, AN2 Therapeutics: Grant/Research Support Carolyn M. Shoen, PhD, AN2 Therapeutics: Grant/Research Support MRK Alley, PhD, ABBOTT LABS: Stocks/Bonds|ABBVIE: Stocks/Bonds|AN2 Therapeutics: Author on epetraborole patent|AN2 Therapeutics: Salary|AN2 Therapeutics: Ownership Interest|AVANOS MED INC: Stocks/Bonds|NABRIVA THERAPEUTICS PLC: Stocks/Bonds|NOVARTIS AG: Stocks/Bonds Michael H. Cynamon, MD, AN2: Grant/Research Support|AN2: Grant/Research Support.