The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis
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 elimi...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41467-025-56146-9 |
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| author | 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 Kerstin Walter |
| author_facet | 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 Kerstin Walter |
| author_sort | Andreas Römpp |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-711ad436a22e4af4a30f74d92daa1049 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-711ad436a22e4af4a30f74d92daa10492025-01-19T12:30:24ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-025-56146-9The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosisAndreas Römpp0Axel Treu1Julia Kokesch-Himmelreich2Franziska Marwitz3Julia Dreisbach4Nadine Aboutara5Doris Hillemann6Moritz Garrelts7Paul J. Converse8Sandeep Tyagi9Sina Gerbach10Luzia Gyr11Ann-Kathrin Lemm12Johanna Volz13Alexandra Hölscher14Leon Gröschel15Eva-Maria Stemp16Norbert Heinrich17Florian Kloss18Eric L. Nuermberger19Dominik Schwudke20Michael Hoelscher21Christoph Hölscher22Kerstin Walter23Bioanalytical Sciences and Food Analysis, University of BayreuthBioanalytical Sciences and Food Analysis, University of BayreuthBioanalytical Sciences and Food Analysis, University of BayreuthDivision of Bioanalytical Chemistry, Research Center Borstel, Leibniz Lung CenterThematic Translational Unit Tuberculosis, German Center for Infection Research (DZIF), Partner Site Munich-BayreuthDivision of Bioanalytical Chemistry, Research Center Borstel, Leibniz Lung CenterNational and WHO Supranational Reference Center for Mycobacteria, Research Center BorstelThematic Translational Unit Tuberculosis, German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-RiemsCenter for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University School of MedicineCenter for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University School of MedicineTransfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, Leibniz-HKIRobotic-assisted Discovery of Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, Leibniz-HKIThematic Translational Unit Tuberculosis, German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-RiemsDivision of Infection Immunology, Research Center Borstel, Leibniz Lung CenterDivision of Infection Immunology, Research Center Borstel, Leibniz Lung CenterBioanalytical Sciences and Food Analysis, University of BayreuthBioanalytical Sciences and Food Analysis, University of BayreuthThematic Translational Unit Tuberculosis, German Center for Infection Research (DZIF), Partner Site Munich-BayreuthTransfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, Leibniz-HKICenter for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University School of MedicineDivision of Bioanalytical Chemistry, Research Center Borstel, Leibniz Lung CenterThematic Translational Unit Tuberculosis, German Center for Infection Research (DZIF), Partner Site Munich-BayreuthThematic Translational Unit Tuberculosis, German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-RiemsThematic Translational Unit Tuberculosis, German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-RiemsAbstract 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.https://doi.org/10.1038/s41467-025-56146-9 |
| spellingShingle | 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 Kerstin Walter The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis Nature Communications |
| title | The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis |
| title_full | The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis |
| title_fullStr | The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis |
| title_full_unstemmed | The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis |
| title_short | The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis |
| title_sort | clinical stage drug btz 043 accumulates in murine tuberculosis lesions and efficiently acts against mycobacterium tuberculosis |
| url | https://doi.org/10.1038/s41467-025-56146-9 |
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