SBIR-STTR Award

Occidiofungin is a cyclic nonribosomally synthesized antifungal peptide with submicromolar fungicidal activity against a broad spectrum of fungi. Occidiofungin is produced by the Gram- negative 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.

Public Health Relevance Statement:
Project Narrative The proposal addresses the need for the development of a novel broad spectrum antifungal for the treatment of systemic fungal infections. We will isolate natural analogs and produce semi-synthetic analogs of the antifungal occidiofungin. This works is essential for identifying a lead compound for preclinical studies that are needed for filing an Investigational New Drug (IND) application.

Project Terms:
Acids; Address; alternative treatment; Amines; Amino Acids; Anabolism; analog; Antifungal Agents; Apoptosis; Asparagine; base; Binding; Biological; Burkholderia; Candida albicans; Candida albicans resistance; Candida glabrata; Caspofungin; Cell Death; Cell Line; Cells; Chemicals; Chlorine; Data; Development; Dose; drug candidate; Elements; Engineering; Ensure; expectation; experience; Fluconazole; fungus; gene product; Goals; Gram-Negative Bacteria; Human; improved; In Vitro; Industrial fungicide; Infection; interest; Investigational Drugs; Investigational New Drug Application; Kidney; Killings; Kinetics; Knowledge; Lead; Libraries; Life; meetings; Methods; microorganism; Mouse Cell Line; Mus; Mycoses; novel; novel therapeutic intervention; novel therapeutics; overexpression; Oxygen; pathogen; Pathway interactions; Patients; Peptide Synthesis; Peptides; Phase; Population; preclinical development; preclinical study; Preclinical Testing; Predisposition; Primary carcinoma of the liver cells; Property; Rattus; Research; Serum; Solid; Structure-Activity Relationship; success; sugar; Testing; Therapeutic; therapeutic development; therapy outcome; Time; Toxic effect; Tyrosine; Work; Xylose; Yeasts

Occidiofungins (A-D) are cyclic nonribosomally synthesized antifungal peptides with submicromolar fungicidal activity against a broad spectrum of fungi. Optimization of the production and isolation of occidiofungins from liquid cultures has been performed. The production and isolation of predominantly one analog, called occidiofungin B (OCF001), supports its commercial development as a novel antifungal therapeutic. Several of the benchmarks used to evaluate the development of a novel therapeutic have been met with OCF001. OCF001 is a potent antifungal against fluconazole and caspofungin-resistant Candida species. It was also shown to be effective at inhibiting Candida auris at 0.25 ?g/ml. The antifungal triggers cell death by inducing apoptosis in yeast cells and was shown to have minimal toxicity in mice dosed with 2 mg/kg in a 28-day toxicity study. Furthermore, OCF001 was demonstrated to be an effective antifungal treatment for vaginal yeast infections in mice. All these studies point to the need to further the preclinical development of this novel compound. OCF001, along with very few antifungal compounds, have met any of these benchmarks, and therefore it holds promise as a potential antifungal therapeutic agent. The goal of this application is to complete the pre-Investigational New Drug (pre-IND) enabling and IND enabling studies for the development of an antifungal product for the treatment of systemic and vaginal yeast infections.

Public Health Relevance Statement:
Project Narrative The proposal addresses the need for the development of novel broad-spectrum antifungal products for vulvovaginal yeast and invasive yeast infections. The studies proposed are essential for filing two Investigational New Drug Applications (INDAs).

Project Terms:
Address; analog; Anti-Infective Agents; Antifungal Agents; Apoptosis; Benchmarking; Binding Proteins; Burkholderia; Candida; Caspofungin; Cell Cycle Kinetics; Cell Death; Cells; Chemicals; Clinical; clinical development; clinically relevant; Development; Disease; Dose; drug candidate; Drug Kinetics; efficacy study; expectation; experience; Exposure to; Fluconazole; Formulation; Fungal Drug Resistance; fungus; Goals; Human; improved; In Vitro; in vivo; Industrial fungicide; Infection; Investigational Drugs; Investigational New Drug Application; Knowledge; Lead; Liquid substance; Maximum Tolerated Dose; Methods; Minimum Inhibitory Concentration measurement; Modeling; mouse model; Mus; Mycoses; Natural Products; novel; novel therapeutic intervention; novel therapeutics; pathogenic fungus; patient population; Patient-Focused Outcomes; Peptides; Periodicity; Pharmaceutical Preparations; pharmacokinetics and pharmacodynamics; Pharmacology; pre-clinical; preclinical development; Preclinical Drug Development; Predisposition; Process; Production; Property; Regimen; Research; Resistance; Resistant candida; Route; Serum; Structure; Testing; Therapeutic; Therapeutic Agents; therapy outcome; Toxic effect; Toxicology; United States Food and Drug Administration; vaginal candidiasis; yeast infection; Yeasts