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In vitro activity of epetraborole, a novel LeuRS inhibitor, alone and in combination against rapidly growing non-tuberculous mycobacteria

M S DeStefano(1) M RK Alley(2) C M Shoen(1) M H Cynamon(1)

1:Veterans Health Research Institute, Syracuse, NY 13210, USA; 2:AN2 Therapeutics Inc., Menlo Park, CA, USA

Rapidly growing mycobacteria (RGM) are intrinsically drug resistant, leading to complicated and often unsuccessful long-term treatment for infections due to these pathogens. Treatment generally includes a macrolide, but inducible and mutational resistance are problematic. Epetraborole (EBO) is a boron-containing, oral inhibitor of bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis. We determined the MIC values of EBO and comparator agents against several strains of RGM including Mycobacteriodes abscessus (MABS), Mycobacteroides chelonae (MC) and Mycolicibacterium fortuitum (MF). Ten of the MABS isolates were further tested in vitro against drug combinations in a checkerboard assay.

Thirty-nine MABS, ten MC and ten MF isolates were tested in cation-adjusted Muller Hinton broth according to CLSI standards. In addition to EBO, clarithromycin (CLR), amikacin (AMK), clofazimine (CFZ), cefoxitin (CFX), linezolid (LZD) and tigecycline (TIG) were tested. EBO was combined with either CLR, AMK, CFZ, CFX, LZD, TIG or imipenem (IMP) in the checkerboard assay. Synergy, additive effects, indifference, or antagonism was characterized using EUCAST criteria.

EBO has potent in vitro activity versus RGM with a MIC₅₀ and MIC₉₀ of 0.06 µg/mL. Also, EBO activity was not affected by resistance to macrolides, aminoglycosides or oxazolidinones. In the checkerboard assay, no antagonisms were observed, and all the combinations tested resulted in indifference when definitive calculations were made. The potent in vitro activity of EBO supports further investigation of EBO as a potential therapy for RGM infections.

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