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

Christopher G Pierce,Alexander T Powell,Anna L Lazzell,Jose L Lopez-Ribot,Stanton F Mchardy,Ashok K Chaturvedi,Stephen P Saville

doi:10.1038/npjbiofilms.2015.12

Abstract

Background/Objectives:Candida albicans 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 C. albicans biofilm formation, and conducted a series of follow-up studies to examine the in vitro and in vivo activity of the identified compounds.Results:The screen identified a novel series of diazaspiro-decane structural analogs that were largely represented among the bioactive compounds. Characterization of the leading compound from this series indicated that it inhibits processes associated with C. albicans virulence, most notably biofilm formation and filamentation, without having an effect on overall growth or eliciting resistance. This compound demonstrated in vivo 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 antivirulence approaches against C. albicans and other fungal infections that would be less likely to foster the emergence of resistance.

Highlights

Candida albicans is generally acquired early in neonatal life and becomes a common commensal of the human oral, vaginal and gastrointestinal tracts, where it normally causes little or no damage to the host
The key properties of compounds in this library are novelty, diversity and ease of follow-up, and small molecules in this library generally have favorable pharmacological characteristics and meet very stringent ‘drug-like’ properties. Compounds in this library were provided as individual stock solutions in 96-well microtiter plates in 10 mM concentrations in dimethyl sulfoxide (DMSO), and the plates are bar-coded for automation and rapid hit identification
A large-scale chemical library screen identifies a series of small molecule inhibitors of C. albicans biofilm formation

Summary

Introduction

Candida albicans is generally acquired early in neonatal life and becomes a common commensal of the human oral, vaginal and gastrointestinal tracts, where it normally causes little or no damage to the host.

Results

Conclusion