Monoclonal antibodies against DNA-binding tips of DNABII proteins disrupt biofilms in vitro and induce bacterial clearance in vivo

EBioMedicine. 2016 Aug;10:33-44. doi: 10.1016/j.ebiom.2016.06.022. Epub 2016 Jun 16.

Abstract

The vast majority of chronic and recurrent bacterial diseases are attributed to the presence of a recalcitrant biofilm that contributes significantly to pathogenesis. As such, these diseases will require an innovative therapeutic approach. We targeted DNABII proteins, an integral component of extracellular DNA (eDNA) which is universally found as part of the pathogenic biofilm matrix to develop a biofilm disrupting therapeutic. We show that a cocktail of monoclonal antibodies directed against specific epitopes of a DNABII protein is highly effective to disrupt diverse biofilms in vitro as well as resolve experimental infection in vivo, in both a chinchilla and murine model. Combining this monoclonal antibody cocktail with a traditional antibiotic to kill bacteria newly released from the biofilm due to the action of the antibody cocktail was highly effective. Our results strongly support these monoclonal antibodies as attractive candidates for lead optimization as a therapeutic for resolution of bacterial biofilm diseases.

Keywords: Histone like protein (HU); Integration host factor (IHF); Nontypeable Haemophilus influenzae; Otitis media; Pseudomonas aeruginosa; Respiratory tract infection.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / pharmacology*
  • Antibody Specificity / immunology
  • Bacterial Infections / drug therapy
  • Bacterial Infections / immunology*
  • Bacterial Infections / microbiology*
  • Bacterial Physiological Phenomena / drug effects*
  • Biofilms / drug effects*
  • Chinchilla
  • Disease Models, Animal
  • DnaB Helicases / antagonists & inhibitors*
  • DnaB Helicases / chemistry
  • Male
  • Mice
  • Models, Molecular
  • Otitis Media / drug therapy
  • Otitis Media / immunology
  • Otitis Media / microbiology
  • Otitis Media / pathology
  • Peptides / antagonists & inhibitors
  • Peptides / chemistry
  • Peptides / metabolism
  • Pneumonia, Bacterial / drug therapy
  • Pneumonia, Bacterial / immunology
  • Pneumonia, Bacterial / microbiology
  • Pneumonia, Bacterial / pathology
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs*
  • Reproducibility of Results

Substances

  • Anti-Bacterial Agents
  • Antibodies, Monoclonal
  • Peptides
  • DnaB Helicases