2148. In vitro Potency of a Leucyl-tRNA Synthetase Inhibitor, MRX-6038, Against Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium abscessus

Abstract Background The family of Mycobacteriaceae contains hundreds of species, some causing diseases in humans. The most well-known is Mycobacterium tuberculosis (Mtb), the causative agent for tuberculosis. Approximately 2 billion people are infected with M. tuberculosis. Drug-resistant strains of M. tuberculosis have emerged in the last 30 years, making the development of newer, effective drugs important. Non-tuberculous mycobacteria (NTM) cause difficult to treat infections. M. abscessus (Mabs) and M. avium (MAC) fall within this category. Drug-resistance and/or drug tolerance is a serious hurdle in trying to control NTM infections. The goal of this study was to evaluate the in vitro activity of a novel leucyl-tRNA synthetase inhibitor, MRX-6038, against Mtb, MAC, and Mabs. Methods MRX-6038, epetroborole (EBO), and GSK656 (GSK) was provided by MicuRx Pharmaceutical Co., Ltd. Clarithromycin (CLR) and isoniazid (INH) were purchased from Biosyth Ltd and Sigma-Aldrich Chemical Company, respectively. Stock solutions were dissolved in 100% DMSO and frozen at -20oC until used. Drugs were serially diluted in cation adjusted Mueller-Hinton broth (CAMHB) (Mabs), CAMHB with 5% OADC (MAC), and 7H9 Broth with 10% OADC (Mtb) in microtiter plates for MIC evaluation in duplicate. Wells were inoculated with ∼ 1.25 x 105 CFU/ml of bacteria. Plates were incubated for 4-5 (Mabs), 7 (MAC), or 14 (Mtb) days at 37oC in ambient air. The MIC is defined as the lowest concentration of drug that yielded no visible turbidity. Results The MIC50 and MIC90 (µg/ml) of the MAC isolates against CLR, EBO, and MRX-6038 were 1 and 4, 1 and 8, and 1 and 8, respectively. The MIC50 and MIC90 of the Mabs isolates against CLR, EBO, and MRX-6038 were 8 and 16, 0.125 and 0.25, and 0.25 and 0.25, respectively. The MIC50 and MIC90 of the Mtb isolates against INH, GSK, and MRX-6038 were 1 and 8, 0.06 and 0.06, and 0.5 and 1, respectively. Many of the Mtb isolates used were known to be MDR strains. Conclusion The in vitro activity of MRX-6038 was quite promising against Mabs, MAC, and Mtb. Based on work by others, MRX-6038 has shown encouraging in vivo activity against Mabs in mice. The next steps will be to determine the in vivo activity against both MAC and Mtb infection in mice. Disclosures Wen Wang, PhD, MicuRx Pharmaceuticals: Employee of