Noninflammatory 97-amino acid High Mobility Group Box 1 derived polypeptide disrupts and prevents diverse biofilmsResearch in context
Jaime D. Rhodes,
Aishwarya Devaraj,
Frank Robledo-Avila,
Sabarathnam Balu,
Lauren Mashburn-Warren,
John R. Buzzo,
Santiago Partida-Sanchez,
Lauren O. Bakaletz,
Steven D. Goodman
Affiliations
Jaime D. Rhodes
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
Aishwarya Devaraj
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
Frank Robledo-Avila
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
Sabarathnam Balu
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
Lauren Mashburn-Warren
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
John R. Buzzo
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
Santiago Partida-Sanchez
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA; Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
Lauren O. Bakaletz
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA; Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA; Corresponding author. 700 Children's Drive, WA5009, Columbus, OH, 43205, USA.
Steven D. Goodman
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA; Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA; Corresponding author. 700 Children's Drive, WA5021, Columbus, OH, 43205, USA.
Summary: Background: Bacterial biofilm communities are embedded in a protective extracellular matrix comprised of various components, with its' integrity largely owed to a 3-dimensional lattice of extracellular DNA (eDNA) interconnected by Holliday Junction (HJ)-like structures and stabilised by the ubiquitous eubacterial DNABII family of DNA-binding architectural proteins. We recently showed that the host innate immune effector High Mobility Group Box 1 (HMGB1) protein possesses extracellular anti-biofilm activity by destabilising these HJ-like structures, resulting in release of biofilm-resident bacteria into a vulnerable state. Herein, we showed that HMGB1's anti-biofilm activity was completely contained within a contiguous 97 amino acid region that retained DNA-binding activity, called ‘mB Box-97’. Methods: We engineered a synthetic version of this 97-mer and introduced a single amino acid change which lacked any post-translational modifications, and tested its activity independently and in combination with a humanised monoclonal antibody that disrupts biofilms by the distinct mechanism of DNABII protein sequestration. Findings: mB Box-97 disrupted and prevented biofilms, including those formed by the ESKAPEE pathogens, and importantly reduced measurable proinflammatory activity normally associated with HMGB1 in a murine lung infection model. Interpretation: Herein, we discuss the value of targeting the ubiquitous eDNA-dependent matrix of biofilms via mB Box-97 used singly or in a dual host-augmenting/pathogen-targeted cocktail to resolve bacterial biofilm infections. Funding: This work was supported by NIH/NIDCD R01DC011818 to L.O.B. and S.D.G. and NIH/NIAID R01AI155501 to S.D.G.
