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

Title data

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. Vol. 31 (September 2020) Issue 11 . - pp. 2277-2286.
ISSN 1879-1123
DOI: https://doi.org/10.1021/jasms.0c00235

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Keywords: MALDI imaging; Tuberculosis; Drugs; Sample preparation; High-resolution
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Biology > Chair Bioanalytical Sciences and Food Analytics > Chair Bioanalytical Sciences and Food Analytics - Univ.-Prof. Dr. Andreas Römpp
Graduate Schools > Bayreuth Graduate School of Mathematical and Natural Sciences (BayNAT) > Molecular Biosciences
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 500 Natural sciences
500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
600 Technology, medicine, applied sciences > 610 Medicine and health
Date Deposited: 24 Nov 2020 07:38
Last Modified: 24 Nov 2020 07:38
URI: https://eref.uni-bayreuth.de/id/eprint/60282