Abstract

The human opportunistic pathogen Pseudomonas aeruginosa produces copious quantities of the secondary metabolite pyocyanin (PYO). PYO has recently been shown to interact with the aryl hydrocarbon receptor (AhR), a transcription factor controlling expression of a number of genes, including the cytochrome P450 CYP1A family involved in fluoroquinolone antibiotic clearance. In this study, we investigated whether Pseudomonas aeruginosa could influence the metabolism of ciprofloxacin through human CYP1A2 induction. Primary human hepatocytes were exposed to 1-100 uM PYO, with high concentrations resulting in apparent cytotoxicity. Treatment with 5 uM PYO led to a 6.2-fold change in CYP1A2 mRNA and a 3.6-fold increase in oxociprofloxacin metabolite formation. Our results suggest that sub-toxic concentrations of PYO induce CYP1A2 expression and increase ciprofloxacin metabolism, which could lead to sub-efficacious antibiotic concentrations and further drive resistance. This finding directs us to a novel mechanism by which Pseudomonas aeruginosa may escape antimicrobial therapy by hijacking host xenobiotic metabolism pathways.