Peptidomimetic Compounds that Inhibit Porphyromonas gingivalis Colonization of the Oral Cavity.

Objectives: The adherence of P. gingivalis to commensal streptococci such as S. gordonii is an initial event that promotes colonization of the oral cavity and as such represents an ideal point for therapeutic intervention. We previously identified a peptide (BAR) that potently inhibits this interaction and the goal of this study was to design, synthesize and evaluate small molecule mimetics of BAR.
Methods: Substituted oxazoles and di-substituted triazine scaffolds were synthesized to mimic the NITVK and VXXLL functional motifs of BAR peptide, respectively. Compounds were tested for inhibition of P. gingivals/S. gordonii adherence in vitro using two different biofilm models and in vivo using a murine model of periodontitis. Active compounds were then tested for toxicity against human and murine cell lines.
Results: Thirty four mimetic compounds were synthesized and purified with yields ranging from 26-90%. Compounds were initially tested for inhibition of P. gingivalis adherence using an in vitro two species biofilm model. Four compounds (95, 111, 115 and 122) were potent inhibitors of adherence, exhibiting IC₅₀ values of 2-5μM. These compounds also disrupted pre-formed two- and three-species biofilms in a dose and time dependent manner. In addition, each compound significantly reduced alveolar bone loss in P. gingivalis-infected mice. None of the compounds displayed hemolytic activity or exhibited toxicity towards telomerase immortalized gingival keratinocytes, or HL60 or J774.1 cells.
Conclusions: Small molecule mimetics of BAR peptide were synthesized using oxazole and triazine scaffolds and four compounds potently inhibited P. gingivalis/S. gordonii adherence in vitro and P. gingivalis-mediated alveolar bone loss in vivo. These compounds exhibited no toxicity towards human cell lines. Together, our results suggest that these compounds represent novel therapeutics that may function to reduce or prevent P. gingivalis colonization of the oral cavity.