Title

Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis

UMMS Affiliation

Program in Gene Function and Expression; Small Molecule Screening Facility; Department of Biochemistry and Molecular Pharmacology

Date

8-13-2013

Document Type

Article

Medical Subject Headings

Candida albicans; Cell Adhesion; High-Throughput Screening Assays; Hyphae; Morphogenesis; Piperazines; Small Molecule Libraries

Disciplines

Pathogenic Microbiology

Abstract

Infection by pathogenic fungi, such as Candida albicans, begins with adhesion to host cells or implanted medical devices followed by biofilm formation. By high-throughput phenotypic screening of small molecules, we identified compounds that inhibit adhesion of C. albicans to polystyrene. Our lead candidate compound also inhibits binding of C. albicans to cultured human epithelial cells, the yeast-to-hyphal morphological transition, induction of the hyphal-specific HWP1 promoter, biofilm formation on silicone elastomers, and pathogenesis in a nematode infection model as well as alters fungal morphology in a mouse mucosal infection assay. We term this compound filastatin based on its strong inhibition of filamentation, and we use chemical genetic experiments to show that it acts downstream of multiple signaling pathways. These studies show that high-throughput functional assays targeting fungal adhesion can provide chemical probes for study of multiple aspects of fungal pathogenesis.

Rights and Permissions

Citation: Fazly A, Jain C, Dehner AC, Issi L, Lilly EA, Ali A, Cao H, Fidel PL Jr, Rao RP, Kaufman PD. Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13594-9. doi:10.1073/pnas.1305982110.Link to article on publisher's site

Related Resources

Link to Article in PubMed

Keywords

UMCCTS funding

PubMed ID

23904484