Grant Number: 1 R41 AI131792-01 Principal Investigator: smith, James Project Title: Lead Compound Discovery from Engineered Analogs of Occidiofungin
Occidiofungin is a cyclic nonribosomally synthesized antifungal peptide with submicromolar fungicidal activity against a broad spectrum of fungi. Occidiofungin is produced by the Gramnegative bacterium Burkholderia contaminans. From our structural characterization studies, occidiofungin was determined to have a unique chemical composition. Our studies have also revealed that occidiofungin has a novel mechanism of action. Occidiofungin is a potent antifungal against fluconazole and caspofungin-resistant Candida albicans. Occidiofungin triggers cell death by inducing apoptosis in yeast cells. Occidiofungin has minimal toxicity in mice dosed with 2 mg/kg in a 28 day toxicity study. Furthermore, occidiofungin was shown to reduce Candida glabrata load in the kidneys of infected mice. All these studies point to the need to further the preclinical development of this novel compound. A major need for furthering investigational studies on this unique antifungal compound is the identification of a lead molecule for preclinical testing. The goal of this application is to screen a library of natural and semi-synthetic analogs of occidiofungin for bioactivity testing. The compound that has the best properties will be used in the required preclinical tests that are compulsory before our initial meeting with the FDA. This work is necessary for furthering additional studies aimed at developing the antifungal compound as a new therapeutic.