Inhibition of ergosterol synthesis in Candida albicans by novel eugenol tosylate congeners targeting sterol 14α-demethylase (CYP51) enzyme
Abstract
This study is a continuation and extension of our previous study in which we synthesized seven novel eugenol tosylate congeners (ETC-1 to ETC-7) from a natural compound eugenol and checked their antifungal activity against different isolates of Candida albicans. All these ETCs showed potent antifungal activity to varying degrees. In this study, the aim is to evaluate the effect of most active compounds (ETC-5, ETC-6 and ETC-7) on ergosterol biosynthesis pathway and cellular viability in C. albicans by applying combined approach of in silico and in vitro methodologies. In silico studies were done through all atom molecular mechanics approach and free binding energy estimations, and in vitro study was done by estimating total intracellular sterol content and effect on expression of ERG11 gene. Furthermore, effect on cell viability by these compounds was also tested. Our results demonstrated that these ETCs target ergosterol biosynthesis pathway in C. albicans by inhibiting the lanosterol 14-α demethylase enzyme and also downregulates expression of its related gene ERG11. Furthermore, these ETCs exhibit potent fungicidal effect in cell viability assay, thus overall results advocating the claim that these tosylates have potential to be taken to next level of antifungal drug development.
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Mutations in ERG11 gene and overexpression of ergosterol in plasma membrane contribute to antifungal resistance.
“Furthermore, mutations in the ERG11 gene, which encodes the essential enzyme 14α‐demethylase (Erg11p) for ergosterol biosynthesis, along with overexpression of ergosterol in the plasma membrane, further contribute to antifungal resistance [2, 46].”
From Statins as Antifungal Agents: A Review on Drug Repurposing and Nanotechnology-Driven Delivery Strategies (2025) · cites this paper as [2]
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- Authors
- Lone, S. A., Khan, S., & Ahmad, A.
- Affiliations
- University of the Witwatersrand (ZA)
- National Health Laboratory Service (ZA)
- Corresponding author
- Ahmad, Aijaz
- Venue
- Archives of Microbiology
- Published
- 2019-11-30
- Volume
- 202
- Issue
- 4
- Pages
- 711-726
- ISSN
- 0003-9276 (ISSN-L)
- 0302-8933
- 1432-072X
- OpenAlex
- W2991076163
- Cited by
- 32
- References
- 36
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 2 · 2020: 3
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of the Witwatersrand, Johannesburg (AZMD019)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Keywords
- Candida albicans, ergosterol biosynthesis, sterol 14α-demethylase, CYP51, antifungal agents, fungal viability, molecular docking, free energy calculation, antifungal drug development
- MeSH terms
- Antifungal Agents, Candida albicans, Cell Survival, Ergosterol, Eugenol, Humans, Microbial Sensitivity Tests, Sterol 14-Demethylase, 14-alpha Demethylase Inhibitors
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