Table 2.

Biochemical basis of azole resistance

MechanismCaused by:Comments
Alteration in drug target (14α-demethylase)Mutations which alter drug binding but not binding of the endogenous substrateTarget is active (i.e., can catalyze demethylation) but has a reduced affinity towards azoles
Alteration in sterol biosynthesisLesions in the Δ5(6)-desaturaseResults in accumulation of 14α-methyl fecosterol instead of ergosterol
Reduction in the intercellular concentration of target enzymeChange in membrane lipid and sterols; overexpression of specific drug efflux pumps (CDR1, PDR5, and BENr)Poor penetration across the fungal membrane; active drug efflux
Overexpression of antifungal drug targetIncreased copy number of the target enzymeResults in increased ergosterol synthesis; contributes to cross-resistance between fluconazole and itraconazole