A humanized monoclonal antibody potentiates killing of Pseudomonas aeruginosa by common antibiotics

Objective: Chronic and recurrent cystic fibrosis lung infections, commonly due to the presence of recalcitrant Pseudomonas aeruginosa biofilms, are not effectively cleared with traditional antibiotics, largely due to a structurally sound and protective extracellular DNA matrix that envelopes biofilm-resident bacteria. We recently showed that when extracellular DNA architecture is disrupted by a humanized monoclonal antibody (HuTipMab) directed against the protective epitopes of universal bacterial proteins that serve as linchpins within the lattice (DNABII proteins), resident bacteria are released in a highly sensitive phenotype that renders them vulnerable to killing by host immune effectors and antibiotics. Methods: P. aeruginosa biofilms formed by 3 clinical isolates were incubated with media alone or HuTipMab to generate non-biofilm-associated bacteria (NBfA) or bacteria newly released from biofilm residence (NRel), respectively. Antibiotic susceptibility testing at sub-MIC concentrations was then performed on each bacterial population to determine the sensitivity of NRel to the action of antibiotics compared to their non-biofilm-associated bacteria counterparts. Results: Biofilms formed by three P. aeruginosa clinical isolates were significantly disrupted by HuTipMab prior to treatment with three commonly prescribed antibiotics for people with cystic fibrosis: colistin, aztreonam, or tobramycin. Bacteria newly released from HuTipMab-treated biofilms were significantly more susceptible to killing by each tested antibiotic compared with both their non-biofilm-associated counterparts and those resident within a biofilm. Conclusions: Whereas antibiotics alone do not successfully clear P. aeruginosa from lungs with cystic fibrosis, we herein provide support for a novel approach toward the aforementioned goal that both independently targets biofilm infrastructure and empowers the use of traditional antibiotics.