Our goal is to develop a first-in-class inhibitor of P. gingivalis colonization of oral biofilms as a treatment for periodontitis. Severe periodontitis affects more than 11% of the world's population, resulting in billions of dollars of direct and indirect costs to society, and is associated with a number of chronic conditions including autoimmune, cardiovascular, respiratory, and neurodegenerative diseases1, 2, 4, 5, 7-9. P. gingivalis is considered a causative species in periodontitis that can function to shape the overall microbial community leading to dysbiosis and tissue damage10-13. Clinical research has confirmed that initial P. gingivalis colonization occurs outside the subgingival pocket14-16. P. gingivalis adheres efficiently to supragingival bacteria such as commensal streptococci17-19. This adherence modulates the pathogenic potential of P. gingivalis and drives colonization20-22. Thus, inhibiting the adherence of P. gingivalis to supragingival bacteria represents an excellent approach to reducing and preventing periodontitis. Our project team originally discovered that initial colonization of the oral cavity by P. gingivalis is mediated by the minor fimbrial antigen (Mfa1) of P. gingivalis binding to the surface antigen I/II of Streptococcus gordonii17, 23-25. Subsequently, we identified a domain in antigen I/II essential to this binding26, 27. A synthetic peptide derived from this region, designated BAR, functions as a potent inhibitor of P. gingivalis adherence and formation of biofilms26, 27. In addition, BAR demonstrates inhibition of P. gingivalis virulence by preventing colonization and subsequent alveolar bone loss in mouse models of severe periodontitis20. More recently, we have generated a lead small molecule mimetic of the BAR peptide (called PG95) to target P. gingivalis in periodontitis. PG95 inhibits P. gingivalis colonization of biofilms and prevents bone loss in mouse models of periodontitis, while showing no toxicity to human cells. The assessment of PG95 using in vitro biofilm models and the mouse model of periodontitis has yielded clear potential as a treatment of periodontitis. Based on these results, our goal is to develop a PG95 mouth rinse for the treatment and prevention of periodontitis. This application is designed to develop quality control assays, define a formulation that is transferable to human clinical trials, determine stability in serum and saliva, and demonstrate safety. The specific aims are to: 1) synthesize PG95, develop a potency assay, and demonstrate efficacy in in vitro biofilm models, 2) define an optimal formulation and determine in vitro PK for PG95, and 3) determine the maximum tolerated dose (MTD) of PG95 following oral administration in mice. Completion of these studies will further support the advancement of PG95 towards clinical development.
Public Health Relevance Statement: Project Narrative Severe periodontitis affects over 11% of the world's population, and is characterized by a pathogenic biofilm and chronic inflammation of the tooth supporting tissues7. P. gingivalis is considered a causative species in periodontitis that can function to reshape the oral microbial community leading to dysbiosis and tissue damage28. Development of a safe treatment for periodontitis that specifically targets P. gingivalis colonization without harming the healthy oral microbiome has the potential to significantly improve the health of the world's population.
Project Terms: Oral Administration; Oral Drug Administration; intraoral drug delivery; Affect; Aftercare; After Care; After-Treatment; post treatment; Alveolar Bone Loss; Alveolar Resorption; Periodontal Bone Loss; Periodontal Resorption; inhibitor; Local Anti-Infective Agents; Antiseptics; Local Antiinfective Agents; Topical Anti-Infective Agents; Topical Antiinfective Agents; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antigens; immunogen; Surface Antigens; Cell Surface Antigens; Immunologic Surface Markers; Immunological Surface Markers; Autopsy; necropsy; postmortem; Bacteria; Biochemistry; Biological Chemistry; Biological Assay; Assay; Bioassay; Biologic Assays; Blood; Blood Reticuloendothelial System; Cardiovascular system; Cardiovascular; Cardiovascular Body System; Cardiovascular Organ System; Heart Vascular; circulatory system; Cells; Cell Body; Clinical Research; Clinical Study; Clinical Trials; Dental Calculus; Tartar; Dental Care; Dental Procedure; dental service; Enzyme-Linked Immunosorbent Assay; ELISA; enzyme linked immunoassay; Gastrointestinal tract structure; Alimentary Canal; Digestive Tract; GI Tract; Gastrointestinal Tract; alimentary tract; digestive canal; Goals; Health; Hematology; Human; Modern Man; In Vitro; Inflammation; Investments; Lead; Pb element; heavy metal Pb; heavy metal lead; Methods; Minor; Oral mucous membrane structure; Buccal Mucosa; Mouth Mucosa; Oral Mucosa; oral mucosae; oral mucosal; Mouthwash; Mus; Mice; Mice Mammals; Murine; Persons; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Nerve Degeneration; Nuclear Magnetic Resonance; Peptides; Chronic Periodontitis; Periodontitis; Quality Control; Recurrent; Recurrence; rRNA; Ribosomal RNA; social role; Role; Safety; Saliva; Societies; Solubility; Staining method; Stains; Streptococcus; Time; Tissues; Body Tissues; Tooth structure; Tooth; teeth; Toxicology; United States; Virulence; Work; World Health; Microbial Biofilms; biofilm; Porphyromonas gingivalis; Bacteroides gingivalis; P gingivalis; P. gingivalis; Mediating; base; Organ; improved; Procedures; Chronic; Phase; Biological; biologic; I-antigen; Buccal Cavity; Buccal Cavity Head and Neck; Cavitas Oris; Mouth; Oral cavity; Dental; Blood Serum; Serum; Ingestion; Exposure to; Shapes; S gordonii; S. gordonii; Streptococcus gordonii; Mouth Sore; irritation; Oral; respiratory; success; synthetic peptide; bone loss; aqueous; Toxicities; Toxic effect; novel; Prevention; Position; Positioning Attribute; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Modeling; Sampling; LC/MS; liquid chromatography mass spectrometry; mimetics; Pathogenicity; Molecular Interaction; Binding; preventing; prevent; small molecule; Dose; Adherence; Data; Detection; Direct Costs; Facilities and Administrative Costs; Indirect Costs; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Development; developmental; microbiome; oral biofilm; oral microbiome; design; designing; pathogenic bacteria; bacteria pathogen; bacterial pathogen; Population; Consumption; microbial community; community microbes; mouse model; murine model; population health; Formulation; small molecule inhibitor; histopathological examination; histopathologic examination; reduce symptoms; alleviate symptom; ameliorating symptom; decrease symptom; fewer symptoms; relieves symptoms; symptom alleviation; symptom reduction; symptom relief; clinical development; procedure cost; procedural costs; oral microbial community; oral microbiota; oral microflora; preservation; dysbiosis; dysbacteriosis; dysbiotic; microbial imbalance; side effect; Home; Autoimmune
