Structural dissection and in vivo effectiveness of a peptide inhibitor of Porphyromonas gingivalis adherence to Streptococcus gordonii.
The interaction of the minor fimbrial antigen (Mfa) with streptococcal antigen I/II (e.g., SspB) facilitates colonization of the dental biofilm by Porphyromonas gingivalis. We previously showed that a 27-mer peptide derived from SspB (designated BAR) resembles the nuclear receptor (NR) box protein-protein interacting domain and potently inhibits this interaction in vitro. Here, we show that the EXXP motif upstream of the NR core α-helix contributes to the Mfa-SspB interaction and that BAR reduces P. gingivalis colonization and alveolar bone loss in vivo in a murine model of periodontitis. Substitution of Gln for Pro(1171) or Glu(1168) increased the α-helicity of BAR and reduced its inhibitory activity in vitro by 10-fold and 2-fold, respectively. To determine if BAR prevents P. gingivalis infection in vivo, mice were first infected with Streptococcus gordonii and then challenged with P. gingivalis in the absence and presence of BAR. Animals that were infected with either 10(9) CFU of S. gordonii DL-1 or 10(7) CFU of P. gingivalis 33277 did not show a statistically significant increase in alveolar bone resorption over sham-infected controls. However, infection with 10(9) CFU of S. gordonii followed by 10(7) CFU of P. gingivalis induced significantly greater bone loss (P < 0.01) than sham infection or infection of mice with either organism alone. S. gordonii-infected mice that were subsequently challenged with 10(7) CFU of P. gingivalis in the presence of BAR exhibited levels of bone resorption similar to those of sham-infected animals. Together, these results indicate that both EXXP and the NR box are important for the Mfa-SspB interaction and that BAR peptide represents a potential therapeutic that may limit colonization of the oral cavity by P. gingivalis.
Department of Periodontics, Endodontics and Dental Hygiene, University of Louisville School of Dentistry, 501 South Preston Street, Louisville, KY 40292, USA.
Carlo Amorin
CA
Daep
Elizabeth A
EA
Novak
Richard J
RJ
Lamont
Donald R
DR
Demuth
D000595:Amino Acid Sequence; D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects*; D016866:Bacteroidaceae Infections / Q000188:drug therapy / Q000382:microbiology; D018441:Biofilms / Q000254:growth & development; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000382:microbiology; D005881:Gingiva / Q000166:cytology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D010518:Periodontitis / Q000382:microbiology / Q000517:prevention & control; D016966:Porphyromonas gingivalis / Q000187:drug effects* / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013290:Streptococcal Infections / Q000188:drug therapy / Q000382:microbiology; D054773:Streptococcus gordonii / Q000502:physiology*
D010455:Peptides