Antifungal agents: mechanisms of action
Abstract
Clinical needs for novel antifungal agents have altered steadily with the rise and fall of AIDS-related mycoses, and the change in spectrum of fatal disseminated fungal infections that has accompanied changes in therapeutic immunosuppressive therapies. The search for new molecular targets for antifungals has generated considerable research using modern genomic approaches, so far without generating new agents for clinical use. Meanwhile, six new antifungal agents have just reached, or are approaching, the clinic. Three are new triazoles, with extremely broad antifungal spectra, and three are echinocandins, which inhibit synthesis of fungal cell wall polysaccharides--a new mode of action. In addition, the sordarins represent a novel class of agents that inhibit fungal protein synthesis. This review describes the targets and mechanisms of action of all classes of antifungal agents in clinical use or with clinical potential.
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Polyenes are the oldest class of antifungal agents, dating back to the 1950s, with amphotericin B being the first FDA-approved antifungal for invasive fungal infections including candidiasis.
“The polyenes are the oldest class of antifungal agents, their discovery and development dating back to the 1950s, with amphotericin B being the first ever FDA-approved antifungal for the treatment of invasive fungal infections, including candidiasis [23,24].”
From Antifungal therapy of Candida biofilms: Past, present and future (2023) · cites this paper as [23]
The lack of highly selective targets contributes to the elevated toxicity frequently associated with antifungal therapy.
“this lack of highly selective targets also contributes to the elevated toxicity frequently associated with antifungal therapy [23].”
From Antifungal therapy of Candida biofilms: Past, present and future (2023) · cites this paper as [23]
Azoles target ergosterol by inhibiting its biosynthetic pathway, specifically cytochrome P-450 14-alpha lanosterol demethylase, and are considered fungistatic.
“Azoles also target ergosterol, but by inhibiting its biosynthetic pathway, most specifically the cytochrome P-450 14-alpha lanosterol demethylase, and they are considered fungistatic drugs [23,25].”
From Antifungal therapy of Candida biofilms: Past, present and future (2023) · cites this paper as [23]
Polyene efficacy is severely compromised by intrinsic toxicity, particularly nephrotoxicity, and infusion-related toxicity.
“However, their efficacy is severely compromised by their intrinsic toxicity, particularly nephrotoxicity, and also by infusion-related toxicity [23].”
From Antifungal therapy of Candida biofilms: Past, present and future (2023) · cites this paper as [23]
Azole derivatives were developed mostly in the 1980s and 1990s and represent the largest class of antifungal agents used today in clinical medicine.
“Azole derivatives was the next class of antifungals, developed mostly in the 1980s and 1990s [23,24]. They represent the largest class of antifungal agents used today in clinical medicine [35].”
From Antifungal therapy of Candida biofilms: Past, present and future (2023) · cites this paper as [23]
Statins inhibit an early step in ergosterol synthesis, the reduction of HMG-CoA.
“While the statins inhibit an early step, the reduction of the steroid precursor hydroxymethylglutaryl-CoA (HMG-CoA), azoles inhibit a later enzymatic step, the demethylation of 14 α-lanosterol [11].”
From Inhibition of<i>Candida albicans</i>by Fluvastatin Is Dependent on pH (2009) · cites this paper as [11]
Azoles inhibit a later step in ergosterol synthesis, the demethylation of 14 α-lanosterol.
“While the statins inhibit an early step, the reduction of the steroid precursor hydroxymethylglutaryl-CoA (HMG-CoA), azoles inhibit a later enzymatic step, the demethylation of 14 α-lanosterol [11].”
From Inhibition of<i>Candida albicans</i>by Fluvastatin Is Dependent on pH (2009) · cites this paper as [11]
Both azoles and statins inhibit the synthesis of the major fungal membrane lipid ergosterol.
“An azole drug was chosen for the analysis because both azoles and statins inhibit the synthesis of the major fungal membrane lipid ergosterol.”
From Inhibition of<i>Candida albicans</i>by Fluvastatin Is Dependent on pH (2009) · cites this paper as [11]
A similar growth phenotype was observed in the presence of fluconazole or ketoconazole.
“A similar phenotype was observed in the presence of fluconazole or ketoconazole, drugs belonging to the azole class of antifungals (Fig. 4, C, D, G, and H) (30,31).”
From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [30]
Currently, there are only four major classes of antifungals in clinical use: azoles, polyenes, echinocandins, and pyrimidine analogs.
“Currently, there are only four major classes of antifungals in clinical use: azoles, polyenes, echinocandins, and pyrimidine analogs [10].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [10]
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- Authors
- Odds, F. C., Brown, A. J. P., & Gow, N. A. R.
- Affiliations
- University of Aberdeen (GB)
- Corresponding author
- Odds, Frank C.
- Venue
- Trends in Microbiology
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 11
- Issue
- 6
- Pages
- 272-279
- ISSN
- 0966-842X (ISSN-L)
- OpenAlex
- W2004503571
- Cited by
- 1,202
- References
- 30
- Citations by year
- 2026: 48 · 2025: 55 · 2024: 44 · 2023: 50 · 2022: 73 · 2021: 84 · 2020: 74 · 2019: 73 · 2018: 77 · 2017: 71 · 2016: 62 · 2015: 55 · 2014: 65 · 2013: 47 · 2012: 45
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- antifungal agents, mechanism of action, triazoles, echinocandins, sordarin, fungal cell wall biosynthesis, molecular targets, disseminated fungal infection, immunosuppressive therapy, antifungal drug development
- MeSH terms
- Anti-Bacterial Agents, Antifungal Agents, Fungal Proteins, Fungi, Humans, Indenes, Models, Biological, Models, Molecular, Peptides, Peptides, Cyclic, Sterols, Drug Design, Molecular Structure, Echinocandins
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