Author ORCID Identifier

https://orcid.org/0000-0002-8844-062X

Date Available

12-16-2022

Year of Publication

2022

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

First Advisor

Sylvie Garneau-Tsodikova

Abstract

Periodontal diseases are inflammatory diseases that can lead to damage of the soft tissue and bone supporting the teeth. Gingivitis is the reversible early stage of gum disease, which consist of gums that bleed when brushing or flossing teeth. When left untreated, the preventable but irreversible late stage of periodontal disease, periodontitis, can lead teeth to loosen or even fall out. Oral bacterial species, such as the Gram-negative anaerobic pathogen Porphyromonas gingivalis trigger these inflammatory diseases through oral dysbiosis. P. gingivalis is a keystone pathogen, meaning that the damage caused by P. gingivalis is not proportional to its abundance. Treatment options for periodontitis includes scaling and root planing with an antibacterial agent as adjunct treatment to better improve patient outcomes. The use of broad-spectrum antibacterial agents that do not specially target pathogenic oral bacterial species has led to bacteria that are less susceptible or even resistant to the antibiotics currently used. Therefore, we set out to develop novel antibacterial agents to selectively combat P. gingivalis without disrupting the beneficial commensal oral bacterial species. The FDA-approved drug zafirlukast (ZAF), used for the treatment of asthma, was shown to display antibacterial activity against P. gingivalis. In a previous study, novel 1st generation ZAF derivatives were synthesized and biologically evaluated and were found to display increased activity against P. gingivalis compared to the parent compound ZAF. Through structure-activity relationship (SAR) studies we rationally designed, synthesized, and biologically evaluated novel 2nd and 3rd generation ZAF derivatives that (i) displayed superior antibacterial activity against P. gingivalis 381 or ATCC 33277 and selective activity with little to no growth inhibition of other oral bacterial species, (ii) displayed bactericidal activity with the most active compounds against P. gingivalis, (iii) displayed an increased safety profile with less cytotoxicity against mammalian cells than ZAF, and (iv) displayed the ability to inhibit P. gingivalis biofilm growth. These insights lay the foundation for future studies to test their potential for preventing and treating P. gingivalis-induced periodontal diseases.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.426

Funding Information

A grant from the University of Kentucky Igniting Research Collaborations Pilot Program (to Sylvie Garneau-Tsodikova and Octavio A. Gonzalez) in 2018-2019, Patrick P. DeLuca Pharmaceutical Technology Professorship (to Sylvie Garneau-Tsodikova) in 2020. This work was in part supported by a National Institutes of Health F31 fellowship DEO29661 (to Kaitlind C. Howard)2021-2022.

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