Periodontitis is a widespread and costly disease that is primarily manifest in the oral cavity but is also associated with systemic diseases such as atherosclerosis and rheumatoid arthritis. Although several organisms have been identified as periodontal pathogens, a recent study suggests that Porphyromonas gingivalis may be a """"""""keystone"""""""" pathogen that disrupts host-microbe homeostasis by inducing populational changes in the biofilm that contribute to inflammation. Thus, preventing P. gingivalis colonization of the oral cavity may not only limit periodontitis and have a positive impact on severe systemic diseases, improving the health status of a significant portion of the adult population. The ideal niche for P. gingivalis is the subgingival pocket, but prior to colonizing this niche, P. gingivali associates with streptococci in the supragingival biofilm. This interaction is an ideal target for therapeutic intervention since it represents one of the first events that promotes colonization of the oral cavity by P. gingivalis. The basic science discoveries that form the foundation for this proposal arise from our previous work showing that the association of P. gingivalis with streptococci is driven by a protein-protein interaction. Our mechanistic characterization of this interaction led to the development of a peptide (designated BAR) that potently inhibits P. gingivalis colonization of the oral cavity. However, peptides are not ideal therapeutic agents due to their high cost of production and susceptibility to degradation. This application addresses these shortcomings using a structure-based approach to design and synthesize non-peptide mimetics of BAR.
The first Aim will apply our knowledge of the structure and mechanism of action of BAR to design and chemically synthesize inexpensive peptidomimetic inhibitors of P. gingivalis colonization using an innovative synthetic approach called click chemistry.
The second Aim of this study will assess the biologic activity of the compounds to identify lead compounds that potently inhibit P. gingivalis adherence to streptococci and the formation of P. gingivalis biofilms. The most active lead compounds will subsequently be tested in Aim 3 for inhibition of P. gingivalis virulence using an animal model of periodontitis. Thus, our prior mechanistic studies uniquely position us to design and develop new potential treatments for periodontitis and its systemic sequelae by specifically targeting P. gingivalis colonization of the oral cavity. The inherent stability and low toxicity of click chemistry products may also facilitat the rapid formulation of compounds in a mouth rinse, varnish, or toothpaste that will be suitable for clinical testing.

Public Health Relevance

Periodontitis is a common oral disease that is present in up to 40% of the adult population in the United States. Annual expenditures for treatment and prevention of periodontitis exceed $15 billion. Although periodontitis is primarily manifest in the oral cavity, it is also associated with systemic illnesses such as heart disease and rheumatoid arthritis. An important recent study suggests that Porphyromonas gingivalis may be a keystone pathogen that induces populational changes in the oral biofilm that contribute to inflammation. Thus, limiting P. gingivalis colonization of the oral cavity may have positive impact periodontal health and on other systemic illnesses associates with periodontitis. This multidisciplinary study will use molecular modeling and protein structural information to design and synthesize compounds that specifically target the periodontal pathogen P. gingivalis and block its colonization of the oral cavity. These compounds represent new potential therapies that may control or prevent periodontitis and the systemic illnesses associated with this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE023206-02
Application #
8705487
Study Section
Special Emphasis Panel (ZRG1-MOSS-F (02))
Program Officer
Lunsford, Dwayne
Project Start
2013-07-23
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$375,000
Indirect Cost
$125,000
Name
University of Louisville
Department
Dentistry
Type
Schools of Dentistry
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40202
Tan, Jinlian; Patil, Pravin C; Luzzio, Frederick A et al. (2018) In Vitro and In Vivo Activity of Peptidomimetic Compounds That Target the Periodontal Pathogen Porphyromonas gingivalis. Antimicrob Agents Chemother 62:
Mahmoud, Mohamed Y; Demuth, Donald R; Steinbach-Rankins, Jill M (2018) BAR-encapsulated nanoparticles for the inhibition and disruption of Porphyromonas gingivalis-Streptococcus gordonii biofilms. J Nanobiotechnology 16:69
Patil, Pravin C; Luzzio, Frederick A; Ronnebaum, Jarrid M (2017) Selective alkylation/oxidation of N-substituted isoindolinone derivatives: synthesis of N-phthaloylated natural and unnatural ?-amino acid analogues. Tetrahedron Lett 58:3730-3733
Kalia, Paridhi; Jain, Ankita; Radha Krishnan, Ranjith et al. (2017) Peptide-modified nanoparticles inhibit formation of Porphyromonas gingivalis biofilms with Streptococcus gordonii. Int J Nanomedicine 12:4553-4562
Patil, Pravin C; Luzzio, Frederick A (2017) Unnatural Amino Acid Derivatives through Click Chemistry: Synthesis of Triazolylalanine Analogues. Synlett 28:1729-1732
Patil, Pravin C; Luzzio, Frederick A (2017) m-Chloroperbenzoic acid-oxchromium (VI)-mediated cleavage of 2,4,5-trisubstituted oxazoles. Tetrahedron Lett 58:1280-1282
Patil, Pravin C; Luzzio, Frederick A (2017) The intramolecular click reaction using 'carbocontiguous' precursors. Tetrahedron 73:4206-4213
Patil, Pravin C; Luzzio, Frederick A (2016) Synthesis of extended oxazoles II: Reaction manifold of 2-(halomethyl)-4,5-diaryloxazoles. Tetrahedron Lett 57:757-759
Weigel, W A; Demuth, D R (2016) QseBC, a two-component bacterial adrenergic receptor and global regulator of virulence in Enterobacteriaceae and Pasteurellaceae. Mol Oral Microbiol 31:379-97
Patil, Pravin C; Tan, Jinlian; Demuth, Donald R et al. (2016) 1,2,3-Triazole-based inhibitors of Porphyromonas gingivalis adherence to oral streptococci and biofilm formation. Bioorg Med Chem 24:5410-5417

Showing the most recent 10 out of 12 publications