The Benzimidazole SPR719 Shows Promising Concentration-Dependent Activity and Synergy against Nontuberculous Mycobacteria

Abstract

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is emerging worldwide. Currently recommended multidrug treatment regimens yield poor outcomes and new drugs and regimens are direly needed. SPR719, the active moiety of SPR720 is a new benzimidazole antibiotic with limited data on antimycobacterial activity. We determined MICs and MBCs against 138 clinical and reference strains of M. avium complex (MAC), M. kansasii, M. abscessus, M. xenopi, M. malmoense and M. simiae and determined synergy with antimycobacterial drugs by checkerboard titrations. To study pharmacodynamics, we performed time-kill kinetics assays of SPR719 alone and in combinations against M. avium, M. kansasii and M. abscessus and assessed synergy by response surface analysis according to BLISS independence. SPR719 showed potent activity against MAC (MIC₉₀ 2 mg/L), M. kansasii (MIC₉₀ 0.125 mg/L) and modest activity against M. abscessus (MIC₉₀ 8 mg/L); its activity is bacteriostatic and concentration-dependent. We recorded potential for combination therapy with ethambutol against M. kansasii and M. avium and synergy with clarithromycin against M. abscessus. Ethambutol increased the SPR719 kill rate against M. kansasii but only prevented SPR719 resistance in M. avium. SPR719 is active in vitro against NTM; its activity is strongest against M. kansasii, followed by MAC and M. abscessus. SPR719 shows promise for combination therapy with ethambutol against MAC and M. kansasii and synergy with clarithromycin against M. abscessus. The parent drug SPR720 could have a role especially in MAC pulmonary disease treatment. Further studies in dynamic models and trials are ongoing to advance clinical development.