An engineered peptide derived from the innate immune effector High Mobility Group Box 1 disrupts and prevents dual genera biofilms formed by common respiratory tract pathogens.

Abstract

Bacterial biofilms mediate chronic and recurrent bacterial infections that are extremely difficult to treat by currently available standards of care. In nature, these encased bacterial communities are typically comprised of more than one genus or species. Specifically, in the airway, nontypeable Haemophilus influenzae (NTHI) predominates and is commonly isolated with one or more of the following co-pathogens with which it forms unique relationships: methicillin-resistant Staphylococcus aureus, Burkholderia cenocepacia, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Moraxella catarrhalis. We recently showed that dual genera biofilms comprised of NTHI plus a co-pathogen are disrupted when the biofilm matrix is destabilized by a pathogen-directed strategy that uses a humanized monoclonal antibody directed against the protective domains of bacterial DNABII proteins found at vertices of crossed strands of eDNA within the biofilm matrix. We also recently showed that a peptide synthesized from the host innate immune effector HMGB1, called mB Box-97syn, competitively inhibits binding of the bacterial DNABII proteins to eDNA which thereby also destabilizes single species biofilms to release biofilm-resident bacteria into a transient yet highly vulnerable state that is more effectively cleared by the host innate immune system and/or antibiotics. Here, we expanded upon these studies to assess the ability of host-augmenting mB Box-97syn to both disrupt 2-genera biofilms formed by NTHI plus a common co-pathogen, as well as prevent their formation. Disruption of established 2-genera biofilms ranged from 57-88%, whereas prevention of 2-genera biofilm formation ranged from 65-80% (P=0.002 - P<0.0001). The sobering recalcitrance of chronic and recurrent respiratory tract infections, combined with growing global concern about AMR, demands development of more effective management and prevention options. Ideally, novel treatment strategies would both target the pathogens and augment the host's natural abilities to eradicate them. Herein, we provide additional data to support continued development of the latter concept via demonstration of mB Box-97syn's efficacy against polymicrobial biofilms.