A Novel Anti-infective Therapy for Treating Periodontitis

Project Summary Our goal is to develop a first-in-class inhibitor of P. gingivalis, T. forsythia and T. denticola for the treatment and prevention of periodontitis. These “red complex” bacteria are considered the causative species in periodontitis and function to reshape the oral microbial community, leading to pathogenic biofilm formation and tissue destruction1-4. Severe periodontitis affects more than 11% of the world’s population, resulting in billions of dollars of direct and indirect costs to society, and is associated with a number of chronic conditions including autoimmune, cardiovascular, respiratory, and neurodegenerative diseases5-11. Currently available treatments rely on dental cleaning procedures and antiseptic mouth rinses, or in severe cases, antibiotics or surgery12. These approaches have varied success, are nonspecific, and can result in disruption of the natural oral microbiome. Dental procedures are costly, time consuming, and not preventative. The use of antibiotics and antiseptic mouthwashes are typically short-term and may have side effects such as tartar build up, tooth staining, and mouth sores. Moreover, the use of antibiotics and antiseptics disrupt and destroy the normal healthy oral microbiome, which acts as a barrier to colonization by pathogenic bacteria. Any new treatment and preventative for periodontitis should be effective (reduce symptoms and prevent recurrence), targeted (eliminate the red complex bacteria, preserve healthy microbiome), safe (long-term use with no side effects) and orally administered (easy, home administration). To our knowledge, no current therapy on the market or in development meets these criteria. Recently, our project team discovered a series of novel class IIb microcins that mediate inhibitory activity against a broad range of Gram negative pathogens13. To validate their antimicrobial potential, we heterologously expressed these microcins in E. coli and unequivocally demonstrated their antimicrobial activity against a variety of Enterobacteriaceae, Pseudomonadales, and other pathogens, including multidrug-resistant isolates of Acinetobacter baumannii13. Building from this work, our goal is to identify and develop a potent microcin that inhibits the growth of the red complex bacteria, P. gingivalis, T. forsythia and T. denticola, for treating and preventing periodontitis. The specific aims of this application are: 1) identify the most potent microcin against P. gingivalis, T. forsythia and T. denticola bacteria, 2) produce sufficient quantities of our lead microcins and establish potency and analytical assays, and 3) demonstrate that oral administration of our lead microcin reduces pathogen levels and periodontitis in mice. The identification and development of a microcin as a safe and effective treatment and preventative of periodontitis has the potential to improve the health of millions of people.