In vitro and in vivo activity of Gepotidacin against drug-resistant mycobacterial infections

Abstract

Mycobacterial pathogens including Non-tuberculous mycobacteria (NTM) and M. tuberculosis (Mtb), are pathogens of significant worldwide interest owing to inherent drug resistance to a wide variety of FDA-approved drugs as well as causing a broad range of serious infections. Identifying new antibiotics active against mycobacterial pathogens is an urgent unmet need, especially those antibiotics that can bypass existing resistance mechanisms. In this study, we demonstrate that Gepotidacin, a first-in-class triazaacenapthylene topoisomerase inhibitor, shows potent activity against Mtb and M. fortuitum as well as against other NTMs species, including fluoroquinolone-resistant M. abscessus. Furthermore, Gepotidacin exhibits concentration-dependent bactericidal activity against various mycobacterial pathogens, synergizes with several drugs utilized for their treatment, and reduces bacterial load in macrophages in the intracellular killing assay comparable to amikacin. Additionally, M. fortuitum ATCC 6841 was unable to generate resistance to Gepotidacin in vitro. When tested in a murine neutropenic M. fortuitum infection model, Gepotidacin caused a significant reduction in bacterial load in various organs at 10 fold lower concentration than amikacin. Taken together, Gepotidacin possesses a potentially new mechanism of action that enables it to escape existing resistance mechanisms. Thus, it can be projected as a potent novel lead for the treatment of mycobacterial infections, particularly for NTM, where present therapeutic interventions are very limited.