Molecular interactions and inhibition of the staphylococcal biofilm-forming protein SdrC

Staphylococcus aureus forms biofilms on indwelling medical devices using a variety of cell-surface proteins. There is growing evidence that specific homophilic interactions between these proteins represent an important mechanism of cell accumulation during biofilm formation, but the underlying molec...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 14; pp. 3738 - 3743
Main Authors:	Feuillie, Cécile, Formosa-Dague, Cécile, Hays, Leanne M. C., Vervaeck, Ophélie, Derclaye, Sylvie, Brennan, Marian P., Foster, Timothy J., Geoghegan, Joan A., Dufrêne, Yves F.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 04-04-2017
Subjects:	Bacterial Adhesion Bacterial Proteins - antagonists & inhibitors Bacterial Proteins - chemistry Bacterial Proteins - metabolism Binding Sites Biochemistry, Molecular Biology Biofilms Biological Sciences Biophysics Hydrophobic and Hydrophilic Interactions Life Sciences Models, Molecular Molecules Nerve Tissue Proteins - chemistry Peptides - chemistry Peptides - pharmacology Protein Binding Proteins Single-Cell Analysis Staphylococcus aureus Staphylococcus aureus - physiology Staphylococcus infections inhibition adhesion SdrC biofilms Staphylococcus aureus
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Summary:	Staphylococcus aureus forms biofilms on indwelling medical devices using a variety of cell-surface proteins. There is growing evidence that specific homophilic interactions between these proteins represent an important mechanism of cell accumulation during biofilm formation, but the underlying molecular mechanisms are still not well-understood. Here we report the direct measurement of homophilic binding forces by the serine-aspartate repeat protein SdrC and their inhibition by a peptide. Using single-cell and single-molecule force measurements, we find that SdrC is engaged in low-affinity homophilic bonds that promote cell–cell adhesion. Low-affinity intercellular adhesion may play a role in favoring biofilm dynamics. We show that SdrC also mediates strong cellular interactions with hydrophobic surfaces, which are likely to be involved in the initial attachment to biomaterials, the first stage of biofilm formation. Furthermore, we demonstrate that a peptide derived from β-neurexin is a powerful competitive inhibitor capable of efficiently blocking surface attachment, homophilic adhesion, and biofilm accumulation. Molecular modeling suggests that this blocking activity may originate from binding of the peptide to a sequence of SdrC involved in homophilic interactions. Our study opens up avenues for understanding the role of homophilic interactions in staphylococcal adhesion, and for the design of new molecules to prevent biofilm formation during infection.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC5389287 1C.F., C.F.-D., and L.M.C.H. contributed equally to his work. Author contributions: C.F., C.F.-D., L.M.C.H., O.V., S.D., M.B., T.J.F., J.A.G., and Y.F.D. designed research; C.F., C.F.-D., L.M.C.H., O.V., and S.D. performed research; C.F., C.F.-D., L.M.C.H., O.V., S.D., M.B., T.J.F., J.A.G., and Y.F.D. analyzed data; and C.F., C.F.-D., L.M.C.H., O.V., S.D., M.B., T.J.F., J.A.G., and Y.F.D. wrote the paper. Edited by Richard P. Novick, New York University School of Medicine, New York, NY, and approved February 27, 2017 (received for review October 11, 2016)
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1616805114