Azole Antifungals

The azoles are the largest and most widely used class of antifungal drugs, named for the nitrogen-containing five-membered ring at the core of their structure. They act by blocking the synthesis of ergosterol, the fungal membrane sterol, and span both topical imidazoles and the systemic triazoles that anchor much of modern antifungal therapy.

Definition

Azole antifungals are synthetic agents containing an azole ring that inhibit the fungal enzyme lanosterol 14-alpha-demethylase (CYP51, encoded by ERG11), thereby blocking ergosterol biosynthesis and disrupting the fungal cell membrane; they are subdivided into imidazoles (two ring nitrogens) and triazoles (three).

Scope

This entry covers the chemistry that defines the class (imidazoles versus triazoles), the shared mechanism of ergosterol-synthesis inhibition, the broad spectrum of the systemic triazoles, and the major routes by which fungi become azole-resistant. It is a reference description of the class and not prescribing guidance.

Core questions

• How does inhibiting one enzyme in the ergosterol pathway impair the fungus?
• What distinguishes imidazoles from triazoles in spectrum and use?
• By what mechanisms do fungi acquire azole resistance?
• Why are drug interactions a recurring theme with the triazoles?

Key concepts

• Lanosterol 14-alpha-demethylase (CYP51 / ERG11) inhibition
• Ergosterol depletion and toxic sterol accumulation
• Imidazoles versus triazoles
• Fungistatic activity against yeasts
• ERG11 mutation and overexpression
• Efflux-pump–mediated resistance
• Cytochrome-P450 drug interactions

Mechanisms

Azoles bind the heme iron of lanosterol 14-alpha-demethylase (CYP51), the enzyme that demethylates lanosterol on the way to ergosterol. Inhibiting it depletes ergosterol and leads to the accumulation of aberrant, toxic methylated sterols, destabilising the fungal membrane; against most yeasts the effect is fungistatic. The triazoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole) are more selective for the fungal over the human enzyme than the older imidazoles, which broadens their systemic use. Resistance arises chiefly through point mutations in ERG11 that lower drug binding, overexpression of ERG11, and up-regulation of efflux transporters that pump the drug out, as detailed by Sheehan and colleagues (1999) and Ghannoum and Rice (1999).

Clinical relevance

The triazoles are central agents in the management of candidiasis and aspergillosis, and azole susceptibility is a routine consideration in interpreting fungal infections (Patterson et al., 2016). Their interactions with the cytochrome-P450 system also make them a frequent topic in pharmacology. This entry describes how the class works and how resistance emerges; it is not a basis for selecting or dosing therapy in an individual.

Epidemiology

Azole resistance is an expanding problem. Acquired azole resistance in Aspergillus fumigatus — partly driven by environmental exposure to agricultural azole fungicides — has been reported across many countries and complicates the treatment of invasive aspergillosis (Lestrade et al., 2019). Azole-resistant and intrinsically less susceptible Candida species are likewise a growing clinical challenge.

History

The imidazoles emerged in the late 1960s and 1970s as mainly topical agents, and the introduction of the systemic triazole fluconazole in the late 1980s transformed antifungal therapy by offering an orally available, comparatively safe drug. Successive triazoles broadened the spectrum to moulds, and the consolidation of the class's mechanism and pharmacology by Sheehan, Hitchcock and Sibley (1999) summarised its rapid maturation.

Debates

How much does environmental fungicide use drive clinical azole resistance?

Azole-resistant Aspergillus fumigatus can arise both in treated patients and in the environment through exposure to agricultural azole fungicides; the relative contribution of this environmental route, and how it should shape stewardship, is an active question.

Key figures

• Dorothy Sheehan
• Christopher Hitchcock
• Mahmoud Ghannoum
• Paul Verweij
• David Denning

Seminal works

• sheehan-1999
• ghannoum-rice-1999

Frequently asked questions

What is the difference between an imidazole and a triazole?

Both are azoles, but imidazoles have two nitrogen atoms in the azole ring and triazoles have three. Triazoles are generally more selective for the fungal target enzyme and are the main systemically used members of the class, whereas many imidazoles are used topically.

Are azoles fungicidal or fungistatic?

Against most yeasts the azoles are fungistatic — they inhibit growth rather than rapidly killing the organism — which is one reason resistance and persistence can develop during prolonged use.