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Römpp, A.* ; Treu, A.* ; Kokesch-Himmelreich, J.* ; Marwitz, F.* ; Dreisbach, J.* ; Aboutara, N.* ; Hillemann, D.* ; Garrelts, M.* ; Converse, P.J.* ; Tyagi, S.* ; Gerbach, S.* ; Gyr, L.* ; Lemm, A.K.* ; Volz, J.* ; Hölscher, A.* ; Gröschel, L.* ; Stemp, E.M.* ; Heinrich, N.* ; Kloss, F.* ; Nuermberger, E.L.* ; Schwudke, D.* ; Hoelscher, M. ; Hölscher, C.* ; Walter, K.*

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

Nat. Commun. 16:826 (2025)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords High-resolution; Antituberculosis Drugs; Sterilizing Activity; Mass; Benzothiazinones; Heterogeneity; Model; Dpre1; Microenvironments; Quantification

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 16, Issue: 1, Article Number: 826

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Global Health (UGH)

Grants German Research Foundation
Leibniz Center for Photonics in Infection Research
German Federal Ministry of Education (BMBF) via the German Center of Infection Research (DZIF)