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Exopolysaccharide biosynthetic glycoside hydrolases can be utilized to disrupt and prevent Pseudomonas aeruginosa biofilms

Perrin Baker, Preston J. Hill, Brendan D. Snarr, Noor Alnabelseya, Mathew J. Pestrak, Mark J. Lee, Laura K. Jennings, John Tam, Roman Melnyk, Matthew R. Parsek, Donald C. Sheppard, Daniel J. Wozniak, P. Lynne Howell
doi: https://doi.org/10.1101/032714
Perrin Baker
1Program in Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
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Preston J. Hill
2Departments of Microbial Infection & Immunity, Microbiology, Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA
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Brendan D. Snarr
3Departments of Medicine, Microbiology and Immunology; Infectious Diseases in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montréal, Québec, H4A 3J1, Canada
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Noor Alnabelseya
1Program in Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
4Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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Mathew J. Pestrak
2Departments of Microbial Infection & Immunity, Microbiology, Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA
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Mark J. Lee
3Departments of Medicine, Microbiology and Immunology; Infectious Diseases in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montréal, Québec, H4A 3J1, Canada
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Laura K. Jennings
5Department of Microbiology, University of Washington, Seattle, Washington, USA
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John Tam
1Program in Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
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Roman Melnyk
1Program in Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
4Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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Matthew R. Parsek
5Department of Microbiology, University of Washington, Seattle, Washington, USA
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Donald C. Sheppard
3Departments of Medicine, Microbiology and Immunology; Infectious Diseases in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montréal, Québec, H4A 3J1, Canada
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Daniel J. Wozniak
2Departments of Microbial Infection & Immunity, Microbiology, Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA
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P. Lynne Howell
1Program in Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
4Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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  • For correspondence: howell@sickkids.ca
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Abstract

Bacterial biofilms are a significant medical challenge as they are recalcitrant to current therapeutic regimes. A key component of biofilm formation in the opportunistic human pathogen Pseudomonas aeruginosa is the biosynthesis of the exopolysaccharides Pel and Psl, which are involved in the formation and maintenance of the structural biofilm scaffold and protection against antimicrobials and host defenses. Given that the glycoside hydrolases – PelAh and PslGh – encoded in the pel and psl biosynthetic operons, respectively, are utilized for in vivo exopolysaccharide processing, we reasoned that these would provide specificity to target P. aeruginosa biofilms. Evaluating these enzymes as potential therapeutics, we demonstrate that these glycoside hydrolases selectively target and degrade the exopolysaccharide component of the biofilm matrix and that nanomolar concentrations of these enzymes can both prevent biofilm formation as well as rapidly disrupt preexisting biofilms in vitro. This treatment was effective against clinical and environmental P. aeruginosa isolates and reduced biofilm biomass by 58–94%. These non-cytotoxic enzymes potentiated antibiotics as the addition of either enzyme to a sub-lethal concentration of colistin reduced viable bacterial counts by 2.5 orders of magnitude. Additionally, PelAh was able to increase neutrophil killing by ~50%. This work illustrates the feasibility and benefits of using bacterial exopolysaccharide biosynthetic glycoside hydrolases and synthetic biology to develop novel anti-biofilm therapeutics.

Footnotes

  • ↵* Research described in this paper is supported by operating grants from the Canadian Institutes of Health Research (CIHR) (#43998 to P.L.H., #123306 to D.C.S., #286650 to R.A.M., and #81361 to P.L.H. and D.C.S.), Cystic Fibrosis Canada (CFC) (D.C.S. and P.L.H.), the National Institutes of Health (R01AI097511 to D.J.W. and 2R01AI077628 to M.R.P.) and the Natural Sciences and Engineering Research Council of Canada (RGPIN 418405 to R.A.M.). P.B. has been supported in part by a CFC postdoctoral fellowship and a Banting Fellowship from CIHR. B.D.S has been supported by graduate scholarships from CFC and CIHR. L.K.J. is the recipient of an American Heart Association Postdoctoral Fellowship (14POST20130017). P.L.H is the recipient of a Canada Research Chair.

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Posted November 26, 2015.
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Exopolysaccharide biosynthetic glycoside hydrolases can be utilized to disrupt and prevent Pseudomonas aeruginosa biofilms
Perrin Baker, Preston J. Hill, Brendan D. Snarr, Noor Alnabelseya, Mathew J. Pestrak, Mark J. Lee, Laura K. Jennings, John Tam, Roman Melnyk, Matthew R. Parsek, Donald C. Sheppard, Daniel J. Wozniak, P. Lynne Howell
bioRxiv 032714; doi: https://doi.org/10.1101/032714
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Exopolysaccharide biosynthetic glycoside hydrolases can be utilized to disrupt and prevent Pseudomonas aeruginosa biofilms
Perrin Baker, Preston J. Hill, Brendan D. Snarr, Noor Alnabelseya, Mathew J. Pestrak, Mark J. Lee, Laura K. Jennings, John Tam, Roman Melnyk, Matthew R. Parsek, Donald C. Sheppard, Daniel J. Wozniak, P. Lynne Howell
bioRxiv 032714; doi: https://doi.org/10.1101/032714

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