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Investigation of quorum sensing in C. albicans
The dimorphic fungus Candida albicans produces extracellular farnesol which acts as a quorum-sensing molecule (QSM) to suppress filamentation. Of four possible geometric isomers of farnesol, only the E,E isomer possesses QSM activity. We tested number of natural and synthetic analogs of farnesol for their activity in an N-acetylglucosamine-induced differentiation assay for germ tube formation (GTF). Modified structural features include the nature of the head group, chain length, presence or absence of the three double bonds, substitution of a backbone carbon by S, O, N, and Se heteroatoms, presence or absence of a 3-methyl branch, as well as the bulkiness and the hydrophobic tail. ^ In order to elucidate localization a putative receptor we prepared ten polyenes typified by 3,7,11-trimethyl-2,4,6,8,10-dodecapentenaldehyde oxime. Four of the ten analogs display strong quorum-sensing activity in the human pathogen Candida albicans, also they are fluorescent. Therefore oxime anti-4 is demonstrated to be useful for confocal fluorescence microscopic imaging of fungal cells. ^ Also, we have investigated of a series of farnesol analogs replacing the primary alcohol head group with several classes of heterocycles. High levels of quorum-sensing activity were associated with several types of heterocycles. Two non toxic analogs were tested in C. albicans inoculated immune-challenged mice. One of the two analogs has been shown to perfectly emulate farnesol in vivo behavior, which unfortunately includes an increase of C. Albicans virulence in the mice. ^ In an attempt to isolate putative farnesol binding receptor we synthesized of affinity media designed to isolate a putative farnesol receptor or binding protein in C. albicans. The approach rests on a new class of farnesol analogs, which maintain the acidic head group and farnesyl-like backbone known from our earlier studies to be necessary for quorum sensing, but which also allow for covalent chemical linkage of the head group to an affinity support. In preliminary results, affinity chromatography of the total protein extract of C. albicans resulted in selective retention of a handful of proteins. Mass spectrometry of some of eluted proteins reveals two matches against known fungal proteins. ^
Chemistry, Biochemistry|Chemistry, Organic
Shchepin, Roman V, "Investigation of quorum sensing in C. albicans" (2006). ETD collection for University of Nebraska - Lincoln. AAI3233745.