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Bioaccumulation of therapeutic drugs by human gut bacteria

Title data

Klünemann, Martina ; Andrejev, Sergej ; Blasche, Sonja ; Mateus, Andre ; Phapale, Prasad ; Devendran, Saravanan ; Vappiani, Johanna ; Simon, Bernd ; Scott, Timothy A. ; Kafkia, Eleni ; Konstantinidis, Dimitrios ; Zirngibl, Katharina ; Mastrorilli, Eleonora ; Banzhaf, Manuel ; Mackmull, Marie-Therese ; Hövelmann, Felix ; Nesme, Leo ; Brochado, Ana Rita ; Maier, Lisa ; Bock, Thomas ; Periwal, Vinita ; Kumar, Manjeet ; Kim, Yongkyu ; Tramontano, Melanie ; Schultz, Carsten ; Beck, Martin ; Hennig, Janosch ; Zimmermann, Michael ; Sévin, Daniel C. ; Cabreiro, Filipe ; Savitski, Mikhail M. ; Bork, Peer ; Typas, Athanasios ; Patil, Kiran R.:
Bioaccumulation of therapeutic drugs by human gut bacteria.
In: Nature. (2021) .
ISSN 1476-4687
DOI: https://doi.org/10.1038/s41586-021-03891-8

Abstract in another language

Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry with an Emphasis on Biophysical Chemistry > Chair Biochemistry with an Emphasis on Biophysical Chemistry - Univ.-Prof. Dr. Janosch Hennig
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 10 Sep 2021 05:43
Last Modified: 06 Oct 2021 06:57
URI: https://eref.uni-bayreuth.de/id/eprint/67004