Natural Product Protease Inhibitors: Therapeutics for Virulence of Oral Pathogens

DESCRIPTION (provided by applicant): Oral infections associated with the gingival margin and subgingival sulcus lead to host inflammatory responses. Gingivitis is primarily a response to the bacteria in plaque. This disease affects nearly everyone in the population, at some time during their life. Periodontitis is a multifactorial disease that encompasses the hard and soft tissue, microbial colonization (with/without invasion), inflammatory responses, and adaptive immune responses. Periodontal inflammation and tissue destruction result from variations in the subgingival bacterial ecology that trigger deleterious host responses, with current evidence suggesting altered production and/or release of an array of destructive host mediators that lead to tissue destruction. However, recent studies have supported that certain putative oral pathogens produce a array of physiologic gene products (e.g. proteases) that have the capacity to engage and stimulate various host cell receptors resulting in a substantially enhanced synthesis of biomolecules that have been implicated in tissue destruction (e.g. IL-1ss, TNF1). Thus, while strategies of combating gingivitis are primarily designed to be managed by mechanical and/or nonspecific antimicrobial therapies to decrease the overall magnitude of bacterial challenge in the plaque; targeting periodontitis requires additional considerations relative to unique features of the microbial composition of the biofilms, and potentially critical host cell signaling mechanisms that may be unique to these pathogens. This STTR proposal is focusing on a strategy to identify natural plant-based agents that will inhibit proteases from significant oral pathogens, P. gingivalis, T. denticola, and T. forsythia. These proteases have been shown to relate to disease sites, in vitro growth and survival, production of inflammatory mediators, and in vivo virulence. Thus, interfering with the activity of these crucial molecules should provide an innovative new strategy to biologically interfere with infection and disease processes provoked by these oral pathogens. Gingivitis and periodontitis affect as large a proportion of the global population as any disease(s) known to mankind. Thus, identifying and developing more effective therapeutic regimens targeting aspects of the chronic infection and inflammation would provide a significant benefit to these individuals. Specific Aims are to document the effect of select natural products on the growth, host cell triggering, and virulence capacity of these bacteria. PUBLIC HEALTH RELEVANCE: This STTR proposal aims to evaluate natural products for their ability to improve oral health by developing therapeutic treatments for gingival inflammation and tissue distruction. Specific Aims are to isolate and analyze natural products with anti-proteases properties to treat oral infections/diseases.