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bioRxiv · 10.1101/2024.03.18.585558

Transformation of the drug ibuprofen by Priestia megaterium: Reversible glycosylation and generation of hydroxylated metabolites

Hinzke, T.·Schlüter, R.·Mikolasch, A.·Zühlke, D.·Müller, P.·Riedel, K.·Lalk, M.·Becher, D.·Sheikany, H.·Schauer, F.
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Abstract

As one of the most-consumed drugs worldwide, ibuprofen (IBU) reaches the environment in considerable amounts as environmental pollutant, necessitating studies of its further biotransformation as potential removal mechanism. Therefore, we screened bacteria with known capabilities to degrade aromatic environmental pollutants, belonging to the genera Bacillus, Priestia (formerly also Bacillus) Paenibacillus, Mycobacterium, and Cupriavidus, for their ability to transform ibuprofen. We identified five transformation products, namely 2-hydroxyibuprofen, carboxyibuprofen, ibuprofen pyranoside, 2-hydroxyibuprofen pyranoside, and 4-carboxy--methylbenzene-acetic acid. Based on our screening results, we focused on ibuprofen biotransformation by Priestia megaterium SBUG 518 with regard to structure of transformation products and bacterial physiology. Biotransformation reactions by P. megaterium involved (A) the hydroxylation of the isobutyl side chain at two positions, and (B) conjugate formation via esterification with a sugar molecule of the carboxylic group of ibuprofen and an ibuprofen hydroxylation product. Glycosylation seems to be a detoxification process, since the ibuprofen conjugate (ibuprofen pyranoside) was considerably less toxic than the parent compound to P. megaterium SBUG 518. Based on proteome profile changes and inhibition assays, cytochrome P450 systems are likely crucial for ibuprofen transformation in P. megaterium SBUG 518. The toxic effect of ibuprofen appears to be caused by interference of the drug with different physiological pathways, including especially sporulation, as well as amino acid and fatty acid metabolism. ImportanceIbuprofen is a highly consumed drug, and, as it reaches the environment in high quantities, also an environmental pollutant. It is therefore of great interest how microorganisms transform this drug and react to it. Here, we screened several bacteria for their ability to transform ibuprofen. Priestia megaterium SBUG 518 emerged as highly capable and was therefore studied in greater detail. We show that P. megaterium transforms ibuprofen via two main pathways, hydrolyzation and reversible conjugation. These pathways bear resemblance to those in humans. Ibuprofen likely impacts the physiology of P. megaterium on several levels, including spore formation. Taken together, P. megaterium SBUG 518 is well suited as a model organism to study bacterial ibuprofen metabolism.

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Hinzke, T., Schlüter, R., Mikolasch, A., Zühlke, D., Müller, P., Riedel, K., Lalk, M., Becher, D., Sheikany, H., Schauer, F.. 2024-03-19. Transformation of the drug ibuprofen by Priestia megaterium: Reversible glycosylation and generation of hydroxylated metabolites. https://doi.org/10.1101/2024.03.18.585558

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