Drug Metab Dispos. 2025 Oct 21;53(12):100184. doi: 10.1016/j.dmd.2025.100184. Online ahead of print.
ABSTRACT
The significance of the gut microbiome on drug metabolism has been demonstrated, yet much less is known about the pathobiome’s potential impact on systemic drug metabolism outside of the β-lactam antibiotics, especially for bacterial species prone to multidrug resistance, which often leads to acute or chronic infections. CYP107S1, a cytochrome P450 (P450) from the opportunistic pathogen Pseudomonas aeruginosa, which exhibits substrate promiscuity and allosteric features, was able to tightly bind (Kd, app of 0.755 μM) and rapidly metabolize with high affinity (Km of 1.63 μM) the nonsteroidal anti-inflammatory drug celecoxib. It formed the same hydroxy metabolite as human CYP2C9, the primary enzyme responsible for the metabolism of this selective cyclooxygenase-2 inhibitor. In liquid cultures of the P. aeruginosa PAO1 strain expressing a relatively high level CYP107S1 during the initial bacterial growth phase, dosing of celecoxib resulted in an increase in the hydroxyl product formation over time, attesting to translation from the P450 in vitro recombinant drug-metabolizing activity to live bacterial cultures. Furthermore, the celecoxib metabolite formation by the CYP107S1 recombinant enzyme or in PAO1 culture was partially inhibited by the pan-CYP inhibitor 1-aminobenzotriazole and exhibited preincubation time-dependency characteristics. Thus, P. aeruginosa CYP107S1 capability to metabolize drugs continues to expand, driving new knowledge and potential for new useful substrate probes to study P450 function and regulation in P. aeruginosa. SIGNIFICANCE STATEMENT: This study provides further insights into the metabolic ability of CYP107S1, a cytochrome P450 enzyme belonging to the azetidine biosynthetic gene cluster of Pseudomonas aeruginosa, which is capable of metabolizing the nonsteroidal anti-inflammatory drug celecoxib, further widening the promiscuity feature of the enzyme and offering a novel probe to study its regulation in the PAO1 strain of P. aeruginosa.
PMID:41237685 | DOI:10.1016/j.dmd.2025.100184