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

Abstract

As one of the most-consumed drugs worldwide, ibuprofen (IBU) reaches the environment in considerable amounts as environmental pollutant, necessitating studies of its biotransformation as potential removal mechanism. Here, 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 seven transformation products, namely 2-hydroxyibuprofen, carboxyibuprofen, ibuprofen pyranoside, 2-hydroxyibuprofen pyranoside, 4-carboxy-α-methylbenzene-acetic acid, 1-[4-(2-hydroxy-2-methylpropyl)phenyl]ethanone, and 2-hydroxyibuprofenmethyl ester. Based on our screening results, we focused on ibuprofen biotransformation by Priestia megaterium SBUG 518, to identify structures of transformation products, and to shed light on the drug’s impact on bacterial physiology. Biotransformation reactions by P. megaterium SBUG 518 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 appear to be central 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, especially sporulation.