Disruption of ergosterol biosynthesis,growth, and the morphological transition in <Emphasis Type="Italic">Candida albicans</Emphasis> by sterol methyltransferase inhibitors containing sulfur at C-25 in the sterol side chain |
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Authors: | Ragu?Kanagasabai Wenxu?Zhou Jialin?Liu Thi?Thuy?Minh Nguyen Phani?Veeramachaneni Email author" target="_blank">W?David?NesEmail author |
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Affiliation: | (1) Department of Chemistry and Biochemistry, Texas Tech University, 79409 Lubbock, Texas |
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Abstract: | The sterol substrate analog 25-thialanosterol and its corresponding sulfonium salt were evaluated for their ability to serve
as antifungal agents and to inhibit sterol methyltransferase (SMT) activity in Candida albicans. Both compounds inhibited cell proliferation, were fungistatic, interrupted the yeastlike-form to germ-tube-form transition,
and resulted in the accumulation of zymosterol and related Δ24-sterols concurrent with a decrease in ergosterol, as was expected for the specific inhibition of SMT activity. Feedback on
sterol synthesis was evidenced by elevated levels of cellular sterols in treated vs. control cultures. However, neither farnesol
nor squalene accumulated in significant amounts in treated cultures, suggesting that carbon flux is channeled from the isoprenoid
pathway to the sterol pathway with minor interruption or redirection until blockage at the C-methylation step. Activity assays using solubilized C. albicans SMT confirmed the inhibitors impair SMT action. Kinetic analysis indicated that 25-thialanosterol inhibited SMT with the
properties of a time-dependent mechanismbased inactivator K
i of 5 =gmM and apparent k
inact of 0.013 min−1, whereas the corresponding sulfonium salt was a reversible-type transition state analog exhibiting a K
i of 20 nM. The results are interpreted to imply changes in ergosterol homeostasis as influenced by SMT activity can control
growth and the morphological transition in C. albicans, possibly affecting disease development. |
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Keywords: | |
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