A novel small molecule inhibitor of Candida albicans biofilm formation, filamentation and virulence with low potential for the development of resistance

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.

An Immunomodulatory Peptide Confers Protection in an Experimental Candidemia Murine Model

“…Treatment of candidemia with frontline antifungal drugs can fail due to the lack of a supportive immune response, development of renal toxicity, and biofilm-mediated antifungal resistance (18)(19)(20). To overcome these issues, host defense peptides (HDPs) represent promising molecules due to their combined antimicrobial and immunomodulatory activities.…”

Assessment and Optimizations of Candida albicans In Vitro Biofilm Assays

“…The findings from these assays were then verified using in vivo models (13)(14)(15)(16)(17)(18)(19)(20)(21). Likewise, in vitro assays have been used as the initial step to identify compounds that inhibit and/or disrupt biofilm formation before the compounds are tested for toxicity in cell culture and in in vivo models (22)(23)(24)(25). Although there are variations in methodology among the different in vitro biofilm assays, at the most basic level they all involve similar steps: initial adherence of cells to a surface coupled with washing to remove nonadhered or weakly adhered cells, followed by a growth step that can vary in length depending on the assay.…”

Screening the Pathogen Box for Identification of Candida albicans Biofilm Inhibitors

“…Somewhat intriguingly, this compound displayed increased activity against C. albicans preformed biofilms compared to its activity against planktonic growth. This represents a rather unique characteristic of this compound, in stark contrast to virtually all currently used antifungals as well as some experimental compounds, which consistently show diminished activity against preformed C. albicans biofilms (11,17,26). Therefore, although not entirely specific for the biofilm lifestyle, it would seem that compound MMV688768 targets a process (or processes) that plays a preponderant role in the survival of C. albicans cells within a biofilm compared to their planktonic counterparts.…”