Drug metabolism of ciprofloxacin, ivacaftor, and raloxifene by Pseudomonas aeruginosa cytochrome P450 CYP107S1

Drug metabolism is one of the main processes governing the pharmacokinetics and toxicity of drugs via their chemical biotransformation and elimination. In humans, the liver, enriched with cytochrome P450 (CYP) enzymes, plays a major metabolic and detoxification role. The gut microbiome and its complex community of microorganisms can also contribute to some extent to drug metabolism. However, during an infection when pathogenic microorganisms invade the host, our knowledge of the impact on drug metabolism by this pathobiome remains limited. The intrinsic resistance mechanisms and rapid metabolic adaptation to new environments often allow the human bacterial pathogens to persist, despite the many antibiotic therapies available. Here, we demonstrate that a bacterial CYP enzyme, CYP107S1, from Pseudomonas aeruginosa, a predominant bacterial pathogen in cystic fi brosis patients, can metabolize multiple drugs from different classes. CYP107S1 demonstrated high substrate promiscuity and allosteric properties much like human hepatic CYP3A4. Our fi ndings demonstrated binding and metabolism by the recombinant CYP107S1 of fl uoroquinolone antibiotics (ciprofloxacin and fl eroxacin), a cystic fi brosis transmembrane conductance regulator potentiator (ivacaftor), and a selective estrogen receptor modulator antimicrobial adjuvant (raloxifene). Our in vitro metabolism data were further corroborated by molecular docking of each drug to the heme active site using a CYP107S1 homology model. Our fi ndings raise the potential for microbial pathogens modulating drug concentrations locally at the site of infection, if not systemically, via CYPmediated biotransformation reactions. To our knowledge, this is the fi rst report of a CYP enzyme from a known bacterial pathogen that is capable of metabolizing clinically utilized drugs.