Antifungal agents

Antifungal agents classified on the basis of the site of action in pathogenic fungi.

Azole and polyene anti-fungal agents target ergosterol, the principal cell membrane sterol of many pathogenic fungi.

Azole antifungal agents inhibit 14alpha-demethylase, a fungal cytochrome P450 (CYP) dependent enzyme, that depletes cell membrane ergosterol, impairs membrane fluidity, accumulates toxic 14alpha-methylated sterols, arrests fungal growth ad eventually causes cell death.

Azoles inhibit CYP enzymes and can be responsible for drugs-drug interactions.

Azole fungal target is heme containing pocket on the 14 a-demthylse enzyme, and variances in the confirmation of this binding pocket and the azole structure defines the binding ability of each drug, and in some fungal species, the potential for cross resistance among triazoles.

Itraconazole and posaconazole, derivatives of ketoconazole, extensions of the nonpolar side chains enhances azole binding to a 14 alpha-demethylase apoprotein, resulting in an enhanced spectrum of activity against molds (Mann PA et al).

Voriconazole, is a derivative of fluconazole, has activity against Aspergillus species and other filamentous fungi.

Resistance to triazole antifungal agents is most commonly related to mutations in the azole binding pocket of 14 a-demethylase and or overexpression of MDR1 efflux pumps that expel fluconazole or the multi-drugs ATP- dependent efflux pumps CDR1 and CDR2, which expel all triazoles, leading to cross resistance.

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