Combination treatment to improve mucociliary transport of Pseudomonas aeruginosa biofilms

Abstract

People with muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often have acute or chronic respiratory infections that are difficult to treat due in part to the accumulation of hyperconcentrated mucus within the airway. Mucus accumulation and obstruction promote chronic inflammation and infection and reduce therapeutic efficacy. Bacterial aggregates in the form of biofilms exhibit increased resistance to mechanical stressors from the immune response (e.g., phagocytosis) and chemical treatments including antibiotics. Herein, combination treatments designed to disrupt the mechanical properties of biofilms and potentiate antibiotic efficacy are investigated against mucus-grown Pseudomonas aeruginosa biofilms and optimized to 1) alter biofilm viscoelastic properties, 2) increase mucociliary transport rates, and 3) reduce bacterial viability. A disulfide bond reducing agent (tris(2-carboxyethyl)phosphine, TCEP), a surfactant (NP40), a biopolymer (hyaluronic acid, HA), a DNA degradation enzyme (DNase), and an antibiotic (tobramycin) are tested in various combinations to maximize biofilm disruption. The viscoelastic properties of biofilms are quantified with particle tracking microrheology and transport rates are quantified in a mucociliary transport device comprised of fully differentiated primary human bronchial epithelial cells. The combination of the NP40 with hyaluronic acid and tobramycin was the most effective at increasing mucociliary transport rates, decreasing the viscoelastic properties of mucus, and reducing bacterial viability. Multimechanistic targeting of biofilm infections may ultimately result in improved clinical outcomes, and the results of this study may be translated into future in vivo infection models.

Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response

“…Work has been done to demonstrate that the composition and concentration of airway mucus in CF influences the biophysical properties of P. aeruginosa biofilms, making them more robust and able to withstand physical and chemical challenges ( 112 ). From a therapeutic point of view, impaired mucociliary clearance and mucus accumulation in diseases such as CF limit the penetration and functionality of anti- P. aeruginosa antibiotics ( 113 , 114 ), and targeting mucus specifically with mucolytic therapies has been shown to both improve the function of antibiotics like tobramycin and improve mucociliary transport ( 115 ). It has long been recognized that mucociliary clearance is an important readout for the efficacy of CF therapies ( 116 ), as we are now seeing with new highly effective CFTR modulator therapies (HEMT).…”