In vitro activity and in vivo efficacy against non-tuberculous mycobacteria of SPR719, the active moiety of the novel oral benzimidazole prodrug SPR720

Abstract

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing globally, with Mycobacterium avium complex (MAC) accounting for 80% of cases and Mycobacterium abscessus among the next most prevalent pathogens. Current treatment necessitates long-term administration of poorly tolerated and modestly effective antibiotic combinations, highlighting the need for new oral agents. SPR719, the active moiety of the benzimidazole phosphate prodrug SPR720, inhibits the ATPase subunits of DNA gyrase B, a target with no human homolog and not exploited by current antibiotics. We demonstrated SPR719 activity against MAC (MIC90, 2 {micro}g/mL) and M. abscessus clinical isolates (MIC90, 4 {micro}g/mL), including those resistant to current standard-of-care (SOC) agents. In vivo efficacy of SPR720 was demonstrated against M. avium ATCC 700898 in a chronic C3HeB/FeJ murine model of pulmonary infection, both as a monotherapy and in combination with clarithromycin, ethambutol and rifabutin. SPR720 monotherapy exhibited a dose-dependent reduction in bacterial burden, with the largest reduction observed when combined with clarithromycin and ethambutol. Efficacy of SPR720 was also demonstrated against M. abscessus subspecies abscessus 1513, a virulent multidrug-resistant strain in a prolonged acute model of pulmonary infection in mice. SPR720 monotherapy exhibited a dose-dependent reduction in bacterial burden with further reductions when combined with SOC agents, clarithromycin and amikacin {+/-} clofazimine. Taken together, the in vitro activity of SPR720 against common NTM pathogens in concert with the proof-of-concept efficacy in murine infection models warrants the continued clinical evaluation of SPR720 as a new oral option for the treatment of NTM-PD.