Development of Therapeutics to Treat Candida albicans Biofilm Infections

DESCRIPTION provided by applicant 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 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 andquot drug likeandquot compounds obtained from commercial vendors and proprietary sources a chemically diverse small molecule library consisting of chemical backbones covering a wide range of chemical scaffolds and a novel natural marine products library consisting of over marine products obtained from a collaborator We have currently acquired some preliminary data for initial andquot hitsandquot 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 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 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