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Molecular Pathogenesis

Inhibition of Outer Membrane Proteases of the Omptin Family by Aprotinin

John R. Brannon, David L. Burk, Jean-Mathieu Leclerc, Jenny-Lee Thomassin, Andrea Portt, Albert M. Berghuis, Samantha Gruenheid, Hervé Le Moual
B. A. McCormick, Editor
John R. Brannon
aDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
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David L. Burk
bDepartment of Biochemistry, McGill University, Montreal, Quebec, Canada
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Jean-Mathieu Leclerc
aDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
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Jenny-Lee Thomassin
aDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
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Andrea Portt
aDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
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Albert M. Berghuis
aDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
bDepartment of Biochemistry, McGill University, Montreal, Quebec, Canada
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Samantha Gruenheid
aDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
cMicrobiome and Disease Tolerance Centre, McGill University, Montreal, Quebec, Canada
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Hervé Le Moual
aDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
cMicrobiome and Disease Tolerance Centre, McGill University, Montreal, Quebec, Canada
dFaculty of Dentistry, McGill University, Montreal, Quebec, Canada
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B. A. McCormick
Roles: Editor
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DOI: 10.1128/IAI.00136-15
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ABSTRACT

Bacterial proteases are important virulence factors that inactivate host defense proteins and contribute to tissue destruction and bacterial dissemination. Outer membrane proteases of the omptin family, exemplified by Escherichia coli OmpT, are found in some Gram-negative bacteria. Omptins cleave a variety of substrates at the host-pathogen interface, including plasminogen and antimicrobial peptides. Multiple omptin substrates relevant to infection have been identified; nonetheless, an effective omptin inhibitor remains to be found. Here, we purified native CroP, the OmpT ortholog in the murine pathogen Citrobacter rodentium. Purified CroP was found to readily cleave both a synthetic fluorescence resonance energy transfer substrate and the murine cathelicidin-related antimicrobial peptide. In contrast, CroP was found to poorly activate plasminogen into active plasmin. Although classical protease inhibitors were ineffective against CroP activity, we found that the serine protease inhibitor aprotinin displays inhibitory potency in the micromolar range. Aprotinin was shown to act as a competitive inhibitor of CroP activity and to interfere with the cleavage of the murine cathelicidin-related antimicrobial peptide. Importantly, aprotinin was able to inhibit not only CroP but also Yersinia pestis Pla and, to a lesser extent, E. coli OmpT. We propose a structural model of the aprotinin-omptin complex in which Lys15 of aprotinin forms salt bridges with conserved negatively charged residues of the omptin active site.

FOOTNOTES

    • Received 4 February 2015.
    • Returned for modification 5 March 2015.
    • Accepted 20 March 2015.
    • Accepted manuscript posted online 30 March 2015.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/IAI.00136-15.

  • Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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Inhibition of Outer Membrane Proteases of the Omptin Family by Aprotinin
John R. Brannon, David L. Burk, Jean-Mathieu Leclerc, Jenny-Lee Thomassin, Andrea Portt, Albert M. Berghuis, Samantha Gruenheid, Hervé Le Moual
Infection and Immunity May 2015, 83 (6) 2300-2311; DOI: 10.1128/IAI.00136-15

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Inhibition of Outer Membrane Proteases of the Omptin Family by Aprotinin
John R. Brannon, David L. Burk, Jean-Mathieu Leclerc, Jenny-Lee Thomassin, Andrea Portt, Albert M. Berghuis, Samantha Gruenheid, Hervé Le Moual
Infection and Immunity May 2015, 83 (6) 2300-2311; DOI: 10.1128/IAI.00136-15
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