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

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.hyphal morphogenesis | small molecule screening | fungal pathogens

Usnic acid inhibits biofilm formation and virulent morphological traits of Candida albicans

“…Altogether the above results show that US reduced the EPS of C. albicans biofilm. The property of cell surface hydrophobicity (CSH) among C. albicans cells plays an important role in cell adhesion which helps it to bind to various human epithelial cells and to inert surfaces (Fazly et al 2013). Usnic acid (US) was able to reduce the surface hydrophobicity of C. albicans in a dose dependent manner as shown in MATH assay and further studies will prove if US can prevent adhesion of C. albicans in in vivo models.…”

Fungal Morphogenesis

“…For instance, genes and compounds that control morphogenesis often also control biofilm development (Giacometti et al 2011;Du et al 2012b;Tsang et al 2012;Connolly et al 2013;Fazly et al 2013). Not surprisingly, 68 out of the 122 genes that are involved in biofilm formation are also involved in filamentous growth in C. albicans (Inglis et al 2012).…”

(1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine derivatives suppress Candida albicans virulence by interfering with morphological transition

“…Quorum sensing molecules such as farnesoic acid and cis ‐2‐dodecenoic acid (BDSF) inhibit C. albicans hyphae formation and appear to play a key role in regulating the C. albicans morphological transition (Oh et al ., 2001; Kim et al ., 2002; Boon et al ., 2008; Deng et al ., 2010). The recently identified small molecule filastatin exhibits excellent inhibitory activity against the cell adhesion, morphogenesis and pathogenesis of C. albicans (Fazly et al ., 2013). …”