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

Andreas Römpp (), Axel Treu, Julia Kokesch-Himmelreich, Franziska Marwitz, Julia Dreisbach, Nadine Aboutara, Doris Hillemann, Moritz Garrelts, Paul J. Converse, Sandeep Tyagi, Sina Gerbach, Luzia Gyr, Ann-Kathrin Lemm, Johanna Volz, Alexandra Hölscher, Leon Gröschel, Eva-Maria Stemp, Norbert Heinrich, Florian Kloss, Eric L. Nuermberger, Dominik Schwudke, Michael Hoelscher, Christoph Hölscher and Kerstin Walter ()
Additional contact information
Andreas Römpp: University of Bayreuth
Axel Treu: University of Bayreuth
Julia Kokesch-Himmelreich: University of Bayreuth
Franziska Marwitz: Leibniz Lung Center
Julia Dreisbach: Partner Site Munich-Bayreuth
Nadine Aboutara: Leibniz Lung Center
Doris Hillemann: Research Center Borstel
Moritz Garrelts: Partner Site Hamburg-Lübeck-Borstel-Riems
Paul J. Converse: Johns Hopkins University School of Medicine
Sandeep Tyagi: Johns Hopkins University School of Medicine
Sina Gerbach: Leibniz-HKI
Luzia Gyr: Leibniz-HKI
Ann-Kathrin Lemm: Partner Site Hamburg-Lübeck-Borstel-Riems
Johanna Volz: Leibniz Lung Center
Alexandra Hölscher: Leibniz Lung Center
Leon Gröschel: University of Bayreuth
Eva-Maria Stemp: University of Bayreuth
Norbert Heinrich: Partner Site Munich-Bayreuth
Florian Kloss: Leibniz-HKI
Eric L. Nuermberger: Johns Hopkins University School of Medicine
Dominik Schwudke: Leibniz Lung Center
Michael Hoelscher: Partner Site Munich-Bayreuth
Christoph Hölscher: Partner Site Hamburg-Lübeck-Borstel-Riems
Kerstin Walter: Partner Site Hamburg-Lübeck-Borstel-Riems

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The development of granulomas with central necrosis harboring Mycobacterium tuberculosis (Mtb) 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 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.

Date: 2025
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DOI: 10.1038/s41467-025-56146-9

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