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.