Each year approximately 5% to 10% of all patients admitted to one of 7,000 acute care hospitals in the U.S will develop a health-care associated infection, which translates into a total of 2-4 million nosocomial infections. Although bacterial organisms represent the majority of these infections, fungal infections represent only 10% of all nosocomial infections, yet account for up to 70% of all patient deaths. Of all fungal invasive infections, by far candidiasis remains the most common, now representing the 3rd to 4th most frequent nosocomial infection in hospitals in the US and worldwide, and Candida albicans remains the main etiological agent of candidiasis. Biofilm formations are being increasingly recognized as the main virulence factor contributing to the pathogenesis of candidiasis and are linked to most clinical manifestations. As such, biofilm formation represents a high value target for the development of novel antifungal agents. We used high throughput screening (HTS) techniques to identify small molecule compounds from Chembridge’s NOVACoreTM chemical library, with inhibitory activity on C. albicans biofilm formation. Based on their IC50 values (potency), lack of toxicity and efficacy in animal models of infection we identified several lead structures. These structures were then modified through iterative synthesis to improve on their anti-biofilm activity, physical chemical properties, and in an attempt to identify potential underlying pharmacophores. Several SAR (structure-activity relationship) trends were observed through the alteration of these structures and the results are actively aiding current studies for further improvement on “drug-like” properties and biofilm inhibition.

Development of novel anti-biofilm compounds for the prevention and treatment of Candidiasis

253rd National Meeting (2017)

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