Disruption of ergosterol biosynthesis, growth, and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C-25 in the sterol side chain

Ragu Kanagasabai, Wenxu Zhou, Jialin Liu, Thi Thuy Minh Nguyen, Phani Veeramachaneni, W. David Nes

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 yeast-like-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 mechanism-based inactivator K i of 5 μM and apparent kinact of 0.013 min -1, whereas the corresponding sulfonium salt was a reversible-type transition state analog exhibiting a Ki 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.

Original languageEnglish
Pages (from-to)737-746
Number of pages10
JournalLipids
Volume39
Issue number8
DOIs
StatePublished - Aug 2004

Fingerprint Dive into the research topics of 'Disruption of ergosterol biosynthesis, growth, and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C-25 in the sterol side chain'. Together they form a unique fingerprint.

Cite this