An enoyl-ACP reductase inhibitor, NITD-916, expresses anti-Mycobacterium abscessus activity

Antibiotic therapy for Mycobacterium abscessus infections is challenging due to resistance of the organism to many clinically available antimicrobials. Here, the efficacy of NITD-916, an enoyl-ACP reductase inhibitor, in preventing M. abscessus growth in vitro and in vivo is demonstrated. The minimal inhibitory concentrations (MICs) of NITD-916 for 12 non-tuberculosis mycobacteria (NTM) reference strains and a collection of 194 clinical M. abscessus isolates were determined using the broth microdilution method. Compatibility of NITD-916 with 10 clinically important antibiotics was ascertained by checkerboard assay. The activity of NITD-916 against M. abscessus growing in cultured macrophages was also evaluated. Finally, the potency of NITD-916 in vivo was determined in a mouse model that mimicked an acute pulmonary M. abscessus infection. NITD-916 was bacteriostatic for M. abscessus replicating in vitro, expressing a MIC₅₀ of 0.125 mg/L and a MIC₉₀ of 1 mg/L against the screened clinical isolates. Furthermore, NITD-916 synergized with clarithromycin in treating 2 out of 5 subsp. massiliense strains. NITD-916 was active against M. abscessus replicating in both cultured macrophages and infected mice. The administration of 100 mg/kg NITD-916 for 14 days resulted in a 5.6 log₁₀ colony-forming units (CFUs) reduction in the bacterial load in mouse lung tissue. NITD-916 is active against M. abscessus in vitro and in vivo and may be used potentially to treat M. abscessus diseases.