Journal
NPJ BIOFILMS AND MICROBIOMES
Volume 1, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npjbiofilms.2015.12
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Funding
- PHS from National Institute of Dental & Craniofacial Research [R21DE017294, 1R01DE023510]
- National Institute of Allergy and Infectious Diseases [RO1Al063256]
- Army Research Office of the Department of Defense [W911NF-11-1-0136]
- American Heart Association South Central Affiliate Predoctoral Fellowship [11PRE5300004]
- San Antonio Life Science Institute
- Computational System Biology Core - National Institute on Minority Health and Health Disparities [G12MD007591]
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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.
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