Science and Research

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

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.

  • 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.

Keywords

  • Animals
  • *Mycobacterium tuberculosis/drug effects
  • *Antitubercular Agents/pharmacology/therapeutic use/administration &
  • dosage/pharmacokinetics
  • Mice
  • *Granuloma/drug therapy/microbiology/pathology
  • Humans
  • Tuberculosis/drug therapy/microbiology/pathology
  • Necrosis
  • Disease Models, Animal
  • Female
  • Microbial Sensitivity Tests
  • Mice, Inbred C57BL
Publication details
DOI: 10.1038/s41467-025-56146-9
Journal: Nat Commun
Pages: 826 
Number: 1
Work Type: Original
Location: ARCN, CPC-M
Disease Area: PALI
Partner / Member: HMGU, FZB, KUM
Access-Number: 39827265

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