A Novel Small Molecule Inhibitor of Biofilm Formation, Filamentation and Virulence with Low Potential for the Development of Resistance.

Background/objectives: is the principal causative agent of candidiasis, the most common fungal infection in humans. Candidiasis represents the third-to-fourth most frequent nosocomial infection worldwide, as this normal commensal of humans causes opportunistic infections in an expanding population of immune- and medically-compromised patients. These infections are frequently associated with biofilm formation, which complicates treatment and contributes to unacceptably high mortality rates.

Methods: To address the pressing need for new antifungals we have performed a high content screen of 20,000 small molecules in a chemical library (NOVACore™) to identify compounds that inhibit biofilm formation, and conducted a series of follow-up studies to examine the and activity of the identified compounds.

Results: The screen identified a novel series of diazaspiro-decane structural analogs which were largely represented among the bioactive compounds. Characterization of the leading compound from this series indicated that it inhibits processes associated with virulence, most notably biofilm formation and filamentation, without having an effect on overall growth or eliciting resistance. This compound demonstrated activity in clinically-relevant murine models of both invasive and oral candidiasis and as such represents a promising lead for antifungal drug development. Furthermore, these results provide proof of concept for the implementation of anti-virulence approaches against and other fungal infections that would be less likely to foster the emergence of resistance.