Influence of inhibitors of sterol biosynthesis on growth and sterol metabolism in Candida albicans



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Texas Tech University


Candida albicans was treated with seven antifungal agents designed to inhibit ergosterol biosynthesis. Two types of inhibitors were studied based on their hypothetical mode of action: mechanism-based inactivators, containing either a sulfur or bromine in the sterol side chain and transition state mimics, which contain a nitrogen in the sterol side chain or in the nucleus. The sterol composition of cells treated with the various compounds was determined using three chromatographic techniques, thin-layer chromatography, reverse-phase high-performance liquid chromatography and gas chromatography-mass spectrometry. Additional characterization of the sterol identities was by proton nuclear magnetic resonance spectroscopy and ultra-violet spectroscopy. Ergosterol was found to be the major sterol in control cultures (69%). In treated cells, the dominant effect on sterol biosynthesis was a significant decrease in the amount of ergosterol. The influence of containing a heteroatom in the side chain on sterol methyl transferase activity was evident in aberrant cell morphology of treated cells and a reduction in ergosterol production. Disturbance of the 24-alkyl to 24-desaikyi ratio by as little as 10 % is sufficient to elicit a fimgistatic response. A second class of inhibitor represented by 3p-aminoianosteroi, designed to inhibit the C-4 demethyiation pathway, was found to inhibit growth by impairing lanosterol metabolism. The relationship between ergosterol biosynthesis inhibition action on fungal growth and ergosterol homeostasis is discussed.