Farnesol emulsion for elimination of Pseudomonas aeruginosa biofilm in a 3D airway model of cystic fibrosis

Abstract

Cystic fibrosis (CF), a life-shortening genetic disease, is hallmarked by mucus obstruction, respiratory deficiency, and chronic bacterial infections. Pseudomonas aeruginosa is the most common virulent respiratory pathogen that is detrimental to the overall survival of CF patients. Here we evaluate the efficacy of farnesol emulsion, a broad-spectrum agent recently used to combat P. aeruginosa biofilm infections, for reducing P. aeruginosa infections in CF using a three-dimensional (3D) airway “organ tissue equivalent” (OTE) model. OTEs are fabricated using cells derived from human primary cells sourced from CF donors (CF-OTEs), which accurately recapitulate multiple key traits of human CF airways, including increased mucin accumulation and lower cilium beating frequency, compared to OTEs derived from normal donors (N-OTEs). The OTE model closely approximates the native CF condition to provide a platform where both mucoid and nonmucoid P. aeruginosa establish biofilms. Luminescence quantification and viable bacterial enumeration demonstrated that more P. aeruginosa biofilm mass developed upon CF-OTEs compared to non-CF (normal) OTEs. The capability to establish infection and biofilm formation, without acute tissue toxicity, allows for rapid discrimination of therapeutic efficacy in an accurate, human in vitro model. Farnesol emulsion disrupted P. aeruginosa biofilms in situ and also protected OTE lung cell viability. We propose that the 3D airway OTE infection model is a reliable preclinical tool for CF drug screening, with farnesol emulsion being a prospective drug candidate to treat P. aeruginosa biofilm infections in CF.