Periodontal disease affects approximately 50% of the adult population in the United States and initiates with the establishment of a poly-microbial complex on the tooth surface more commonly known as dental plaque. Coupled with various immunological factors bacterial pathogens can trigger the deterioration of tooth supporting tissues, resulting in tooth loss. In addition to this, poor oral hygiene has been associated with systemic diseases such as infective endocarditis, a potentially lethal infection of the cardiac valves. While the oral cavity contains over 700 species of microorganisms, few species are known to contribute to the onset of periodontal disease. Clinical evidence suggests that Porphyromonas gingivalis plays a significant role in the progression of the disease, expressing numerous virulence factors that aid in the infection. Concerning periodontal disease, we hypothesize narrow spectrum antibiotics may be beneficial. By specifically targeting one of the primary pathogens, one could reduce the destructive factors triggering periodontitis while maintaining a person's healthy flora. Based on previous studies in the benign early colonizer Streptococcus sanguinis, we have knowledge of essential pathways and genes required for microbial growth and survival. With this knowledge in the foreground we believe we have the ability to predict essential gene targets in other microbial species. In our preliminary studies we analyzed these essential pathways to predict essential genes in P. gingivalis. We then compared the predicted essential genes to known essential genes in S. sanguinis and selected the enzyme diaminopimelate dehydrogenase as P. gingivalis "specific", which we confirmed to be essential. A 3D model of the protein has been created based off the crystal structure and is now being studied for its protein and binding properties. To further explore a species-specific drug discovery strategy we propose the following aims: (1) to identify a set of potential enzyme inhibitors utilizing in silico molecular modeling, (2) to determine the efficacy of our candidate antimicrobial compounds through target-based assays and (3) to select for antimicrobial properties through whole-cell based screening. Ultimately, these aims propose to identify a prospective antimicrobial agent specific to the periopathogen P. gingivalis, potentially demonstrating drugability and selectivity within a poly-microbial environment. Once completed, our study may give insight into a novel therapeutic approach when dealing with periodontal disease.
Periodontal disease affects approximately half of the US adult population. While not lethal in itself, poor oral health has been linked to strokes, heart disease and respiratory illnesses. The bacterium Porphyromonas gingivalis is shown to play a key role in the development of gum disease. Therefore, our goal is to discover a prospective antibiotic to target P. gingivalis in order to maintain a healthy oral cavity.
|Stone, Victoria N; Parikh, Hardik I; El-rami, Fadi et al. (2015) Identification of Small-Molecule Inhibitors against Meso-2, 6-Diaminopimelate Dehydrogenase from Porphyromonas gingivalis. PLoS One 10:e0141126|