The clinical-stage drug BTZ-043 accumulates in tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis

Abstract Centrally necrotizing granulomas that harbor Mycobacterium tuberculosis (Mtb) are the hallmark of human tuberculosis (TB). New anti-TB therapies will need to effectively penetrate the cellular and necrotic, non-vascularized compartments of these lesions and reach sufficient concentrations to eliminate Mtb. BTZ‑043 is a novel antibiotic showing good bactericidal activity in humans in a phase IIa trial. Here, we report on the substantial efficacy of BTZ‑043 in the advanced pre-clinical model of interleukin-13-overexpressing mice, which mimic human TB pathology of pulmonary central granuloma necrosis. Accordingly, pulmonary BTZ‑043 concentrations were severalfold above the minimal inhibitory concentration in these mice. The detailed histological characterization of lung granulomas in combination with high resolution MALDI imaging revealed that BTZ‑043 diffuses and accumulates in the cellular compartment, and fully penetrates the necrotic center. In summary, this study is the first visualizing an efficient penetration, accumulation, and retention of a clinical-stage TB drug in human-like centrally necrotizing granulomas.