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Römpp, Andreas ; Treu, Axel ; Kokesch-Himmelreich, Julia ; Marwitz, Franziska ; Dreisbach, Julia ; Aboutara, Nadine ; Hillemann, Doris ; Garrelts, Moritz ; Converse, Paul J. ; Tyagi, Sandeep ; Gerbach, Sina ; Gyr, Luzia ; Lemm, Ann-Kathrin ; Volz, Johanna ; Hölscher, Alexandra ; Gröschel, Leon ; Stemp, Eva-Maria ; Heinrich, Norbert ; Kloss, Florian ; Nuermberger, Eric L. ; Schwudke, Dominik ; Hoelscher, Michael ; Hölscher, Christoph ; Walter, Kerstin:
The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis.
In: Nature Communications.
Bd. 16
(18 Januar 2025)
Heft 1
.
- 826.
ISSN 2041-1723
DOI: https://doi.org/10.1038/s41467-025-56146-9
Angaben zu Projekten
| Projekttitel: |
Offizieller Projekttitel Projekt-ID German Center for Infection Research (DZIF) 02.806 German Center for Infection Research (DZIF) 02.810 German Center for Infection Research (DZIF) 02.814 INST 91/373-1-FUGG Ohne Angabe SFB 1357 Mikroplastik 391977956 Technologie Allianz Oberfranken Ohne Angabe |
|---|---|
| Projektfinanzierung: |
Bundesministerium für Bildung und Forschung Deutsche Forschungsgemeinschaft Andere |
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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.