Identification of small molecule inhibitors targeting Porphyromonas gingivalis interspecies adherence and determination of their in vitro and in vivo efficacy.

Identification of small molecule inhibitors targeting Porphyromonas gingivalis interspecies adherence and determination of their in vitro and in vivo efficacy. Antimicrob Agents Chemother. 2020 Aug 17;: Authors: Roky M, Tan J, Sztukowska MN, Trent JO, Demuth DR Abstract P. gingivalis is one of the primary causative agents of periodontal disease and initially colonizes the oral cavity by adhering to commensal streptococci. Adherence requires the interaction of a minor fimbrial protein (Mfa1) of P. gingivalis with streptococcal antigen I/II (AgI/II). Our previous work identified an AgI/II peptide that potently inhibited adherence and significantly reduced P. gingivalis virulence in vivo, suggesting that this interaction represents a potential target for drug discovery. To develop targeted small molecule inhibitors of this protein-protein interaction, we performed a virtual screen of the ZINC databases to identify compounds that exhibit structural similarity with the two functional motifs (NITVK and VQDLL) of the AgI/II peptide. Thirty three compounds were tested for in vitro inhibition of P. gingivalis adherence and the three most potent compounds, N7, N17 and V8 were selected for further analysis. In vivo efficacy of these compounds was evaluated in a murine model of periodontitis. Treatment of mice with each of the compounds significantly reduced maxillary alveolar bone resorption in infected animals. Finally, a series of cytotoxicit...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research