title: A Novel Small Molecule Inhibitor ofCandida albicansBiofilm Formation, Filamentation and Virulence with Low Potential for the Development of Resistance.
abstract: OBJECTIVE
  Candida albicansis 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 inhibitC. albicansbiofilm formation, and conducted a series of follow-up studies to examine thein vitroandin vivoactivity 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 withC. albicansvirulence, most notably biofilm formation and filamentation, without having an effect on overall growth or eliciting resistance. This compound demonstratedin vivoactivity 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 againstC. albicansand other fungal infections that would be less likely to foster the emergence of resistance.
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, United States of America.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Pierce
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, United States of America.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Chaturvedi
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, United States of America.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Lazzell
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, United States of America.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Powell
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, United States of America.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Saville
authors.affiliation: Department of Chemistry and Center for Innovation in Drug Discovery, The University of Texas at San Antonio, San Antonio, TX 78249, United States of America.
authors.forename: Stanton F
authors.initials: SF
authors.lastname: McHardy
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, United States of America.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Lopez-Ribot
keywords: Candida albicans; anti-virulence; antifungal drugs; biofilms; filamentation; high content screening