A new, broad-spectrum azole antifungal: posaconazole–mechanisms of action and resistance, spectrum of activity
Abstract
Posaconazole, a new triazole antifungal, exerts principally the same mechanism of action as the other azole derivatives, i.e. it inhibits the ergosterol production by binding and inhibiting the lanosterol-14alpha-demethylase which is present in almost all fungi except Pneumocystis and Pythium. Posaconazole has an exquisitely high affinity to this target. Since posaconazole has a chemical structure different from fluconazole and voriconazole, it can interact with an additional domain of the target so that it may inhibit even mutated strains resistant to fluconazole and voriconazole. In addition posaconazole is a bad substrate for efflux pumps in fungi, so it can stay active when other azoles are already inactive. Furthermore, the spectrum of posaconazole is rather large including also some zygomycetes resistant to other azoles. In conclusion, posaconazole is actually the most potent azole derivative used in medicine. A combination of posaconazole with other groups of antifungals may have a favourable effect. There are several methods to test the in vitro activities of posaconazole including the E-test, though interpretive breakpoints are still lacking.
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POS is not a substrate for MDR1 or FLU1 encoded efflux pumps.
“POS is not a substrate for MDR1 or FLU1 encoded efflux pumps (Chau et al. 2004; Hof 2006)”
From Acquisition of cross-azole tolerance and aneuploidy in <i>Candida albicans</i> strains evolved to posaconazole (2022) · cites this paper as Hof 2006
Azoles disrupt the cell membrane by inhibiting lanosterol 14-α-demethylase, an enzyme involved in ergosterol biosynthesis.
“Azoles disrupt the cell membrane by inhibiting the activity of the lanosterol 14-α-demethylase [21], enzyme involved in the biosynthesis of ergosterol (Figure 1).”
From <i>Candida</i>Infections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [21]
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- Authors
- Hof, H.
- Affiliations
- Heidelberg University (DE)
- Corresponding author
- Hof, H.
- ORCID
- Hof, H.
- Venue
- Mycoses
- Publisher
- Wiley
- Published
- 2006-09-06
- Volume
- 49
- Issue
- s1
- Pages
- 2-6
- ISSN
- 0027-5557 (ISSN-L)
- 0933-7407
- 1439-0507
- OpenAlex
- W1975324254
- Cited by
- 116
- References
- 20
- Citations by year
- 2025: 13 · 2024: 5 · 2023: 4 · 2022: 14 · 2021: 10 · 2020: 7 · 2019: 9 · 2018: 9 · 2017: 6 · 2016: 5 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 1
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mycoses (publishedVersion)
- PubMed (publishedVersion)
- 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
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- posaconazole, triazole antifungals, azole antifungals, ergosterol biosynthesis, antifungal resistance, efflux pump resistance, Zygomycetes, fluconazole resistance, voriconazole resistance, combination antifungal therapy, in vitro susceptibility testing, E-test, interpretive breakpoints
- MeSH terms
- Antifungal Agents, Azoles, Fungi, Humans, Microbial Sensitivity Tests, Triazoles, Drug Resistance, Fungal
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