Development of zafirlukast derivatives against Porphyromonas gingivalis

Research project: Gum disease, also known as periodontal disease, is an infection that can lead to damage and inflammation of the gum and bone that surround the teeth. The early stage of gum disease is gingivitis, which consists of gums that bleed when brushing or flossing teeth.

When left untreated the late stage of periodontal disease, periodontitis, can lead to teeth that will loosen or even fall out.

Periodontitis is associated with a Gram-negative anaerobic bacterium called Porphyromonas gingivalis, which is a keystone pathogen, meaning that the damage caused by P. gingivalis is not proportional to its abundance.

The lack of guidelines for selecting an antibiotic regimen for the treatment of periodontitis has led to bacteria that are less susceptible to or even resistant to the antibiotics currently used. Therefore, there is a need for novel antibacterial agents to selectively combat P. gingivalis to treat periodontitis.

Recently, a screening of a drug-repositioning library looking for antibacterial compounds led to the discovery of zafirlukast (ZAF) as a lead compound showing activity against P. gingivalis. For my project I want to develop ZAF derivatives with activity against P. gingivalis. In order to do this, I have come up with three research aims.

The first is to synthesize novel ZAF derivatives with activity against P. gingivalis.

The second aim is to determine the true potential of these derivatives as antibacterial agents through percent growth inhibition, minimum inhibitory concentration, resistance, and cytotoxicity experiments.

If the compounds are found to be potent with low toxicity to mammalian cells, the experiments will provide insight into which functional groups are beneficial or detrimental to the activity of the compounds and allow for further optimization of lead compounds. The third aim is to determine the mechanism of action of ZAF and its derivatives in P. gingivalis.

Training plan: In addition to gaining new technical skills in chemistry, biochemistry, and microbiology, this Fellowship will allow for development of other important skills for my future career in industry (e.g., communication (via poster/oral presentations and writing of manuscripts and grant applications), networking, attendance at conferences, development of leadership and mentoring skills, etc).

Environment: The environment at the University of Kentucky is highly conducive to preparing me for a successful career in industry with state-of-the-art equipment, seminar series, courses, workshops, and opportunities to develop collaborations with other Colleges on campus.