Abstract The development of granulomas with central necrosis harboring Mycobacterium tuberculosis (Mtb) stagg sdm70 is the hallmark of human tuberculosis (TB).New anti-TB therapies need to effectively penetrate the cellular and necrotic 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 lesional BTZ-043 concentrations severalfold above the minimal-inhibitory-concentration and the substantial local efficacy of BTZ-043 in interleukin-13-overexpressing mice, which mimic human TB pathology cocktail tree for sale of granuloma necrosis.High-resolution MALDI imaging further reveals that BTZ-043 diffuses and accumulates in the cellular compartment, and fully penetrates the necrotic center.
This is the first study that visualizes an efficient penetration and accumulation of a clinical-stage TB drug in human-like centrally necrotizing granulomas and that also determines its lesional activity.Our results most likely predict a substantial bactericidal effect of BTZ-043 at these hard-to-reach sites in TB patients.