The yeast Candida albicans is a normal resident of the human digestive tract. It is also the most common fungal pathogen of humans, causing both mucosal and systemic infections, particularly in immune compromised individuals. The majority of new C. albicans infections arise from the presence of persistent C. albicans cells existing in a biofilm. These biofilm-based infections are highly correlated with implanted medical devices, which provide efficient substrates for biofilm formation. There are no products on the market today or in the drug development pipeline that specifically target biofilms. The overall goal of ths Phase I STTR proposal is to begin the development process for biofilm-specific therapeutics as novel treatments of infection against C. albicans biofilms. In this proposal, BioSynesis, Inc. plans to take two strategies to identify biofilm-specific therapeutics: targeted and whole-cell approaches (Aim 1), which will take place simultaneously. The targeted approach is based on the recent identification of the transcriptional network controlling the process of C. albicans biofilm formation discovered by the co-founders of BioSynesis, Inc. We plan to use this knowledge of potential drug targets as a starting point to develop novel biofilm-specific therapeutics. The whole-cell approach is based on high- throughput in vitro screening of existing compound libraries for their abilities to both disrupt and inhibit C. albicans biofilms. These libraries include a small molecule library consisting of over 170,000 "drug-like" compounds obtained from commercial vendors and proprietary sources, a chemically diverse small molecule library consisting of 30,000 chemical backbones, covering a wide range of chemical scaffolds, and a novel natural marine products library consisting of over 4,000 marine products obtained from a collaborator. We have currently acquired some preliminary data for initial "hits" from our library screens, would like to complete our high throughput biofilm screens, and develop some of the leads that we have discovered. We will perform preliminary toxicity assays where we will evaluate whether our lead compounds are toxic to mammalian epithelial cells, and will also perform preliminary in vivo testing of the top lead compounds for their abilities to disrpt and/or prevent biofilm formation in the in vivo rat catheter biofilm model (Aim 2). Completion of these aims will set us up well for a Phase II STTR proposal, where we will refine our chemical drug compositions to improve efficacy and delivery, and thoroughly evaluate the optimized (second generation) lead compounds in the in vivo rat catheter biofilm model for both effectiveness against biofilms and for toxicity. If successful, this work will lead to the development of a new class of biofilm-specific drugs that will change our current clinical practices for treating infections. In principle, our approach could also be taken for other known pathogens, and our drugs may prove efficacious against fungal pathogens with conserved biofilm components.
Public Health Relevance Statement: Public Health Relevance: New therapeutics to disrupt and prevent biofilm formation are urgently needed. The goal of this proposal is to begin the development pathway for biofilm-specific therapeutics as novel treatments of infection against C. albicans biofilms. If successful, this STTR Phase I study will lay the groundwork for the development of a novel class of biofilm-specific drugs that will change our current clinical practices for treating fungal infections.
Project Terms: Animals; Antimicrobial Resistance; base; Biological Assay; Blood; Candida albicans; Catheters; Cell Line; Cells; Chemicals; clinical practice; Complement; Data; deletion analysis; Development; Disease; drug development; Drug resistance; Drug Targeting; Effectiveness; Enzymes; Epithelial Cells; Future; Gastrointestinal tract structure; Gene Targeting; Generations; Goals; Growth; high throughput screening; Human; Immune; Immune system; Implant; improved; In Vitro; in vivo; Individual; Infection; Knowledge; Lead; Libraries; marine natural product; Marines; Marketing; Medical; Medical Device; Microbe; Microbial Biofilms; microorganism; Modeling; Morbidity - disease rate; Mortality Vital Statistics; mutant; Mycoses; Nature; novel; novel therapeutics; pathogen; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; phase 1 study; Poisons; prevent; Process; Property; Protease Inhibitor; Proteins; public health relevance; Rattus; scaffold; screening; Screening procedure; Skin Tissue; Small Business Technology Transfer Research; small molecule; small molecule libraries; Soft Tissue Infections; Source; Surface; Suspension substance; Suspensions; Systemic infection; Testing; Therapeutic; therapeutic development; therapeutic target; Toxic effect; Toxicity Tests; Vendor; Vertebral column; Virulent; Work; Yeasts
