Relationship of Azole Resistance with the Structural Alteration of the Target Sites: Novel Synthetic Compounds for Better Antifungal Activities
Bheru S. Kitawat,
Tapan K. Mukherjee.
Azoles have consistently been recognized as the mainstays of antifungal drugs, amongst which ergosterol
prevails as an integral component of fungal plasma membrane. It is most commonly produced via demethylation of
lanosterol by the cytochrome P450-dependent enzyme lanosterol 14α-demethylase. Azoles exert their antifungal activities
via binding to lanosterol 14 α-demethylase and thereby preventing the demethylation of lanosterol. This leads to the
depletion of demethylated lanosterol (ergosterol) with the concomitant accumulation of methylated sterol precursors
(lanosterol, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol) and deterioration of the membrane integrity,
resulting in fungal growth inhibition. Resistance to azoles is a concern, particularly during the long-term treatment of
fungus mediated cellular complications. To combat azole resistance and to extend the spectrum of treatable pathogens, the
development of novel and more potent azoles, with alteration in active sites has attracted worldwide scientific attention.
With such an insight, this review focuses on antifungal potentials of azole compounds with an emphasis on the
corresponding drug resistance episodes complemented with novel strategies for the development of new generation of
Keywords: Azole, lanosterol, ergosterol, 14-α-lanosterol-demethylase, structure-function relationship, drug resistance.
Rights & PermissionsPrintExport