Preclinical Evaluation of Recombinant Microbial Glycoside Hydrolases as Antibiofilm Agents in Acute Pulmonary Pseudomonas aeruginosa Infection

Abstract

The bacterium Pseudomonas aeruginosa can colonize the airways of patients with chronic lung disease. Within the lung, P. aeruginosa forms biofilms that can enhance resistance to antibiotics and immune defenses. P. aeruginosa biofilm formation is dependent on the secretion of matrix exopolysaccharides, including Pel and Psl.

Targeting Matrix Exopolysaccharides to Disrupt <em>Pseudomonas aeruginosa</em> Biofilms in Cystic Fibrosis

“…Specifically, investigations across many different clinical strains are required to demonstrate whether there is the potential for widespread applicability or whether the promising effects that have been observed are specific to particular bacterial strains. To overcome this high level of specificity, studies bringing these therapies to animal models have focused on co-administration of certain compounds, whether it is a DNase or another glycoside hydrolase [97,124]. Combining therapy of different matrix-degrading enzymes may have many benefits, from targeting multiple EPSs at once and achieving broader therapeutic coverage, to extending the half-life of the compounds, as observed when combining PelAh with PslGh [124].…”

“…To overcome this high level of specificity, studies bringing these therapies to animal models have focused on co-administration of certain compounds, whether it is a DNase or another glycoside hydrolase [97,124]. Combining therapy of different matrix-degrading enzymes may have many benefits, from targeting multiple EPSs at once and achieving broader therapeutic coverage, to extending the half-life of the compounds, as observed when combining PelAh with PslGh [124]. Moreover, there is no reason that antibiotics with different mechanisms of action should all act in additive or synergistic ways with these compounds, and this is illustrated by some of the preliminary in vitro work showing additional benefit when PslGh was administered with the fluoroquinolone ciprofloxacin, but not with the third generation cephalosporin ceftazidime -both commonly used agents in P. aeruginosa infection.…”

“…showed an increase in the number of pulmonary lymphocytes following glycoside hydrolase administration, warranting further study, as these compounds may trigger specific adaptive immune responses over-time. Of critical importance is the hematological dissemination and lethal septicemia that has been seen in animal models if glycoside hydrolases are used in the absence of antibiotics [124]. Additionally, most of the in vivo studies use wound or implant infection models, leaving a gap in knowledge concerning the efficacy of these compounds in pulmonary infection models, which better represent CF lung infection.…”

“…[86]. When combined, PslGh -PelAh improved the penetration and efficacy of ciprofloxacin, tobramycin, colistin, neomycin, and polymyxin, allowing for smaller antibiotic dosages [89,90]. PslGh also works remarkably quickly, completely disrupting all Psl fibers within 5 minutes of administration and triggering sudden biofilm dispersal [82].…”

“…the most comprehensive pre-clinical evaluation of PslGh and PelAh to date, Ostapska et al prophylactically administered PslGh and PelAh intratracheally to mice with P. aeruginosa lung infections with or without antibiotics[89]. They found that the antimicrobial effects of ciprofloxacin, but not ceftazidime, were potentiated when administered every 8 hours following initial treatment with PslGh -PelAh.…”