Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity.

Autor: Snarr BD; Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada.; Department of Medicine, Infectious Diseases and Immunity in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada., Baker P; Program in Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada., Bamford NC; Program in Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada., Sato Y; Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada.; Department of Medicine, Infectious Diseases and Immunity in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada., Liu H; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502., Lehoux M; Department of Medicine, Infectious Diseases and Immunity in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada., Gravelat FN; Department of Medicine, Infectious Diseases and Immunity in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada., Ostapska H; Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada.; Department of Medicine, Infectious Diseases and Immunity in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada., Baistrocchi SR; Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada.; Department of Medicine, Infectious Diseases and Immunity in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada., Cerone RP; Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada.; Department of Medicine, Infectious Diseases and Immunity in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada., Filler EE; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502., Parsek MR; Department of Microbiology, University of Washington, Seattle, WA 98195., Filler SG; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502.; David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90024., Howell PL; Program in Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada; don.sheppard@mcgill.ca howell@sickkids.ca.; Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada., Sheppard DC; Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada; don.sheppard@mcgill.ca howell@sickkids.ca.; Department of Medicine, Infectious Diseases and Immunity in Global Health Program, Centre for Translational Biology, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Jul 03; Vol. 114 (27), pp. 7124-7129. Date of Electronic Publication: 2017 Jun 20.
DOI: 10.1073/pnas.1702798114
Abstrakt: Galactosaminogalactan and Pel are cationic heteropolysaccharides produced by the opportunistic pathogens Aspergillus fumigatus and Pseudomonas aeruginosa , respectively. These exopolysaccharides both contain 1,4-linked N -acetyl-d-galactosamine and play an important role in biofilm formation by these organisms. Proteins containing glycoside hydrolase domains have recently been identified within the biosynthetic pathway of each exopolysaccharide. Recombinant hydrolase domains from these proteins (Sph3 h from A. fumigatus and PelA h from P. aeruginosa ) were found to degrade their respective polysaccharides in vitro. We therefore hypothesized that these glycoside hydrolases could exhibit antibiofilm activity and, further, given the chemical similarity between galactosaminogalactan and Pel, that they might display cross-species activity. Treatment of A. fumigatus with Sph3 h disrupted A. fumigatus biofilms with an EC 50 of 0.4 nM. PelA h treatment also disrupted preformed A. fumigatus biofilms with EC 50 values similar to those obtained for Sph3 h In contrast, Sph3 h was unable to disrupt P. aeruginosa Pel-based biofilms, despite being able to bind to the exopolysaccharide. Treatment of A. fumigatus hyphae with either Sph3 h or PelA h significantly enhanced the activity of the antifungals posaconazole, amphotericin B, and caspofungin, likely through increasing antifungal penetration of hyphae. Both enzymes were noncytotoxic and protected A549 pulmonary epithelial cells from A. fumigatus -induced cell damage for up to 24 h. Intratracheal administration of Sph3 h was well tolerated and reduced pulmonary fungal burden in a neutropenic mouse model of invasive aspergillosis. These findings suggest that glycoside hydrolases can exhibit activity against diverse microorganisms and may be useful as therapeutic agents by degrading biofilms and attenuating virulence.
Competing Interests: Conflict of interest statement: A patent has been filed describing the utility of the glycoside hydrolases as antibiofilm therapeutics (CA2951152 A1, WO2015184526 A1). B.D.S., P.B., N.C.B., P.L.H., and D.C.S. are listed as inventors.
Databáze: MEDLINE
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