Antimicrobial peptide mimetic activity against Candida auris

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Project Summary / Abstract Candida auris is a recently emerged pathogenic fungus, whose infections lead to high mortality in invasive nosocomial infections world-wide. The fungus can persist long-term, and thus can often cause outbreaks. In addition, C. auris exhibits high levels of resistance to all classes of antifungal drugs. Even those strains which are initially susceptible to echinochandins, the treatment of choice, rapidly develop resistance. Thus, there is an urgent need to develop new antifungal drugs to treat this pathogen. 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 them. Unfortunately, they are expensive to produce and are often sensitive to protease digestion. We have recently demonstrated the potent antifungal activity of a series of inexpensive nonpeptidic compounds that mimic AMPs in both structure and activity. These AMP mimetics exhibit strong activity against C. albicans in both planktonic and biofilm forms, as well as against drug-resistant non-albicans Candida clinical isolates. The activity is rapid, and fungicidal against both blastoconidia and hyphal forms, and resistant strains of Candida have failed to be generated, suggesting that they are attractive candidates as drugs to treat C. auris infections. Most recently it was demonstrated that these mimetics exhibit potent in vivo activity in two mouse models of oral candidiasis and in a model of invasive candidiasis, with low in vivo systemic toxicity. Indeed, preliminary data show potent activity of newly designed mimetics against C. auris in vitro. These initial results support the hypothesis that these compounds are active, and non-toxic, and can be developed into novel therapeutic antifungal agents to treat C. auris infections. In order to obtain sufficient data to investigate this in depth, this exploratory study proposes to examine the activity of AMP mimetics against C. auris. To address this, two aims are proposed: 1) Quantify the antifungal activity of select AMP mimetics against C. auris clinical isolates, and evaluate the development of resistance in vitro; 2) Quantify the kinetics and activity of select AMP mimetics in mouse models of C. auris infection. Successful completion of these aims will provide the basis for future studies of these mimetic compounds as a treatment for C. auris, and potentially other emerging fungal pathogens.