Mechanism of azole antifungal drug

Best antifungal drugs. Azole, triazole, polyene

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Azole. Best antifungal antibiotic:

An azole (considered as one of the best antifungal drugs) is a group of antibiotics that destroy the cell membrane of fungi. It inhibits the enzyme called lanosterol 14α-demethylase that is needed for the synthesis of ergosterol which is the main component of the fungi cell membrane. Nowadays various versions of azole are used for different fungal infections like athlete’s foot, fungal nail infections called onychomycosis, vaginal candidiasis.

Structure of an azole:

structure of azole anti fungal antibiotics


Generations of azole:

We know that the generation of different drugs is basically its various derivatives that little bit different functionally, structurally based functional, efficacy, and on nature of bioavailability.

Some of these generations of azole antifungal drugs are as follow:

First-generation                 Second generation                      Third generation

Ketoconazole                    Fluconazole, Itraconazole      Voriconazole, (mostly used).




Chemical properties of azole:

Azoles drugs are five-membered heterocyclic molecule which comprises nitrogen atom and other may be non-carbon atom-like sulfur and oxygen, that are part of the ring. Azole is aromatic in nature and has two double bonds.

Structure-based classification of azoles:

Azoles can be classified into two main groups:

  • When ring of azole contain two nitrogen atoms known as imidazole’s. It include: econazole, tioconazole, miconazole, clotrimazole extra.
  • The second group of azoles has three nitrogen atoms in the aromatic ring which is called triazole for example voriconazole, fluconazole, and itraconazole, Posaconazole.

This two-group, classified based on the presence of nitrogen, are clinically very important for treating a systemic infection caused by various strains of fungi. With the exception of ketoconazole, all imidazole’s are limited for superficial mycoses only. However triazoles is used for both superficial  as well as systemic fungal infection. Another advantage of triazole is higher attraction or affinity to cytochrome p-450 of fungal cells than mammalian cells which enhance safety profile of azole.

The mechanism of azole drugs:


It is necessary to discuss the role of ergosterol before discussing the mechanism of azole drug. We know that ergosterol is a very important component of the cell membrane of fungi and some Protista like trypanosome.  Chemically it is called 5,5-diene oxysterol which is the most abundant sterol in cell membrane of fungi. It performs the same function as cholesterol doing in the animal cell membrane. So the basic function of ergosterol is to regulate the permeability and keep the balanced shape of cells in either cold or hot environments.


Fungi are eukaryotic organisms which possess a unique cell wall and cell membrane that can serve as targets for anti-fungal agents. The Azole family of drugs specifically targets the fungal cell membrane. The cell membrane of fungi is similar to that of other eukaryotic cells and is composed of a lipid bilayer with proteins embedded within it.  A major component of the fungal cell membrane is the presence of sterols which are virtually absent from all prokaryotes including bacteria. In fungi, ergosterol replaces the cholesterol component found in higher eukaryotic cell membranes. This molecule (ergosterol) provides stability and flexibility to the fungal cell membrane.

Lanosterol role in antifungal drugs:

Lanosterol serves as the precursor for the formation of ergosterol. Although many enzymes are involved in the formation of ergosterol, the 14 Alpha demethylase enzyme is responsible for the sea demethylation of lanosterol. It is an essential enzyme that serves as a target for Azole anti- fungal agents. Although some Azoles have an immediate effect of damaging the fungal cell membrane directly their major mechanism of action is by binding to the cytochrome P-450 mediated 14 Alpha demethylase enzymes, thus inhibiting the demethylation of lanosterol and blocking the synthesis of ergosterol. The lack of ergosterol in the fungal cell membrane makes it very unstable and eventually the cell membrane begins to break down and the fungal organism dies.


Mechanism of azole antifungal drug

Resistance against azole drugs:

In Candida spp. and Aspergillus spp. strains there were mold-resistant noted against Posaconazole and voriconazole. The main mechanism of resistance that noted was the alteration of functional groups in the target protein CYP51.

Resistance against the azole antifungal drugs has been found in several species of fungi. Generally, the following kind of resistance arise by certain fungal species against azole drugs:

  • Upregulation of genes that control drug efflux
  • Changes in sterol synthesis or
  • Change in structure of target site to decrease the affinity of azole toward target site like cytochrome p-450 demethylase and these types of resistance have been studied mostly in Candida albicans. In other cases, C. albicans was reported to show high efflux of drugs and reduced influx across the cell membrane. This phenomenon was observed when there was greater expression of CDR genes and the CaMDR1genes that resulted in resistance.
  • Interaction with other drugs:
    Azoles may interact with following drugs like
  • Hapatic CYP as substrate and inhibitors
  • Increase plasma level of some drugs likes digoxin, buspirone, alprazolam, warfarin, cyclosporine, and many other drugs.
  • Co-administered drugs may also decrease the plasma concentration of azoles.
  • Combination of some drugs like tetrabenazine,tioridazine with azole like fluconazole cause contraindication.
  • Route of administration:
  • Azole is available like orally and intravenous form like itraconazole,
  • Fluconazole and ketoconazole taken as oraly in 1-2% or200mg per day.
  • Voriconazole is administered as extemporaneously


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