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Integrating High-Resolution MALDI Imaging into the Development Pipeline of Anti-Tuberculosis Drugs

Titelangaben

Treu, Axel ; Kokesch-Himmelreich, Julia ; Walter, Kerstin ; Hölscher, Christoph ; Römpp, Andreas:
Integrating High-Resolution MALDI Imaging into the Development Pipeline of Anti-Tuberculosis Drugs.
In: Journal of the American Society for Mass Spectrometry. Bd. 31 (2020) Heft 11 . - S. 2277-2286.
ISSN 1879-1123
DOI: https://doi.org/10.1021/jasms.0c00235

Abstract

Successful treatment of tuberculosis (TB) requires antibiotics to reach their intended point of action, i.e., necrotizing granulomas in the lung. MALDI mass spectrometry imaging (MSI) is able to visualize the distribution of antibiotics in tissue, but resolving the small histological structures in mice, which are most commonly used in preclinical trials, requires high spatial resolution. We developed a MALDI MSI method to image antibiotics in the mouse lung with high mass resolution (240k @ m/z 200 fwhm) and high spatial resolution (10 μm pixel size). A crucial step was to develop a cryosectioning protocol that retains the distribution of water-soluble drugs in small and fragile murine lung lobes without inflation or embedding. Choice and application of matrices were optimized to detect human-equivalent drug concentrations in tissue, and measurement parameters were optimized to detect multiple drugs in a single tissue section. We succeeded in visualizing the distribution of all current first-line anti-TB drugs (pyrazinamide, rifampicin, ethambutol, isoniazid) and the second-line drugs moxifloxacin and clofazimine. Four of these compounds were imaged for the first time in the mouse lung. Accurate mass identification was confirmed by on-tissue MS/MS. Evaluation of fragmentation pathways revealed the structure of the double-protonated molecular ion of pyrazinamide. Clofazimine was imaged for the first time with 10 μm pixel size revealing clofazimine accumulation in lipid deposits around airways. In summary, we developed a platform to resolve the detailed histology in the murine lung and to reliably detect a range of anti-TB drugs at human-equivalent doses. Our workflow is currently being employed in preclinical mouse studies to evaluate the efficacy of novel anti-TB drugs.

Weitere Angaben

Publikationsform: Artikel in einer Zeitschrift
Begutachteter Beitrag: Ja
Keywords: MALDI imaging; Tuberculosis; Drugs; Sample preparation; High-resolution
Institutionen der Universität: Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Biologie > Lehrstuhl Bioanalytik und Lebensmittelanalytik > Lehrstuhl Bioanalytik und Lebensmittelanalytik - Univ.-Prof. Dr. Andreas Römpp
Graduierteneinrichtungen > Bayreuther Graduiertenschule für Mathematik und Naturwissenschaften - BayNAT > Molekulare Biowissenschaften
Fakultäten
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Biologie
Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Biologie > Lehrstuhl Bioanalytik und Lebensmittelanalytik
Graduierteneinrichtungen
Graduierteneinrichtungen > Bayreuther Graduiertenschule für Mathematik und Naturwissenschaften - BayNAT
Titel an der UBT entstanden: Ja
Themengebiete aus DDC: 500 Naturwissenschaften und Mathematik > 500 Naturwissenschaften
500 Naturwissenschaften und Mathematik > 540 Chemie
500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie
600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
Eingestellt am: 24 Nov 2020 07:38
Letzte Änderung: 09 Feb 2022 10:04
URI: https://eref.uni-bayreuth.de/id/eprint/60282