The opportunistic human fungal pathogen Candida albicans relies on cell morphological transitions to develop biofilm and invade the host. In the current study, we developed new regulatory molecules, which inhibit the morphological transition of C. albicans from yeast-form cells to cells forming hyphae. These compounds, benzyl α-l-fucopyranoside and benzyl β-d-xylopyranoside, inhibit the hyphae formation and adhesion of C. albicans to a polystyrene surface, resulting in a reduced biofilm formation. The addition of cAMP to cells treated with α-l-fucopyranoside restored the yeast-hyphae switch and the biofilm level to that of the untreated control. In the β-d-xylopyranoside treated cells, the biofilm level was only partially restored by the addition of cAMP, and these cells remained mainly as yeast-form cells.Antibiotics 2020, 9, 10 2 of 11 system. For example, the hyphal glucan consists of a unique cyclic (1-3)-linked polymer backbone with long (1-6)-linked side chains [22]. Hyphae also have less mannan, compared to yeast-form cells [23]. The morphological transition from yeast-form cells to hyphae (i.e., switching) is a complex, tightly regulated process during the biofilm maturation, which is regulated by environmental conditions and quorum sensing molecules such as farnesol and tyrosol [21]. Multiple signaling pathways such as cyclic adenosine monophosphate/protein kinase A (cAMP-PKA), high-osmolarity glycerol (HOG), mitogen-activated protein kinases (MAPK), and several transcriptional factors, Efg1, Bcr1, Ndt80, Cph1, Cph2, Tec1, Nrg1, Rfg1, and Tup1 are known to regulate the morphological transition and hyphal adhesion [1,21,[24][25][26]. Upon stimuli favoring hyphae, the yeast cells produce a germ tube that extends by polarized growth by the activity of membrane-bound vesicles supplying the components of the plasma membrane and cell wall to the growing hyphae [21].Different carbohydrates have been explored for their possibilities to disturb or prevent adhesion, biofilm formation, and the extension of an already existing biofilm of C. albicans [27][28][29][30][31][32][33][34]. In addition, some natural products of plant origin were recently shown to reduce the adhesion of C. albicans and its biofilm formation by inhibiting the yeast-to-hyphae transition [35,36].In this study, we synthesized and tested the effect of simple monosaccharides and glycosides (Chart 1) on C. albicans biofilm development on polystyrene surfaces.