Research Project
7405070
[unreadable] DESCRIPTION (provided by applicant): Oral infections of Candida albicans represent an increasing problem in human health. In immunocompromised individuals, especially those suffering from AIDS, Candidiasis can result in both localized, yet painful lesions in the oral cavity and life-threatening systemic infections. Furthermore, due to the use of standard antifungal treatments, an increasing number of infections are due to non-albicans Candidal (NAC) species. It is thus critical to develop new therapies that can treat both C. albicans infections and those due to NAC. Antimicrobial peptides (AMPs) are naturally occurring, broad-spectrum antimicrobial agents that have been examined recently for their utility as therapeutic antibiotics and antifungals. Chief among their strengths is that microbes do not generally develop resistance to these agents. Unfortunately, they are expensive to produce and are often sensitive to protease digestion. Polymedix, Inc. has developed a series of inexpensive nonpeptidic oligomers and polymers that mimic AMPs in both structure and activity. Preliminary data indicate that some of these compounds exhibit growth inhibitory activity against both C. albicans and oral pathogenic bacteria in vitro. Growth of bacteria in low concentrations of the compounds does not generate resistant strains of bacteria, suggesting that they act in a similar way to the native peptides. The overall hypothesis of this application is that these compounds can form the basis for the development of novel therapies against Candidal infections. The goal of this first phase application is to identify the compound which exhibits the best set of criteria characteristic of a highly active antifungal agent. Toward that goal it is proposed to 1) Establish the optimal in vitro activities of peptide-mimetic compounds against Candida species; 2) Identify factors, such as salivary and serum components, that might modify in vitro activity of the compounds; and 3) Quantify the cytotoxicity of the peptide mimetics against human oral epithelial cells. Successful completion of this phase will result in the identification of a peptide-mimetic compound that exhibit optimal killing of Candida species, with minimal effect on the host. Furthermore, we will have identified potential inhibitors of the activity, and factors that may provide enhanced killing, in order to develop the most appropriate delivery system. We will then be able to use this compound for further studies in animal models of disease for its development as a therapeutic agent. Oral Candidal infections are serious complications found in immunocompromised individuals, such as those suffering from AIDS. Development of safe and effective agents to treat these painful and sometimes life-threatening infections, without the risk of developing resistant strains of Candida, is essential. The compounds to be examined here represent an important advance in the design of antifungal agents for oral applications. [unreadable] [unreadable] [unreadable]
