Abstract
The fungal cytochrome P450 enzyme sterol 14α-demethylase (SDM) is a key enzyme in the ergosterol biosynthesis pathway. The binding of azoles to the active site of SDM results in a depletion of ergosterol, the accumulation of toxic intermediates and growth inhibition. The prevalence of azole-resistant strains and fungi is increasing in both agriculture and medicine. This can lead to major yield loss during food production and therapeutic failure in medical settings. Diverse mechanisms are responsible for azole resistance. They include amino acid (AA) substitutions in SDM and overexpression of SDM and/or efflux pumps. This review considers AA affecting the ligand-binding pocket of SDMs with a primary focus on substitutions that affect interactions between the active site and the substrate and inhibitory ligands. Some of these interactions are particularly important for the binding of short-tailed azoles (e.g., voriconazole). We highlight the occurrence throughout the fungal kingdom of some key AA substitutions. Elucidation of the role of these AAs and their substitutions may assist drug design in overcoming some common forms of innate and acquired azole resistance.
Highlights
The azole drug segment has dominated the global antifungal drug market since the first-generation azoles clotrimazole and miconazole were introduced into the clinic in1960 [1]
Five triazole drugs are available for therapy of systemic fungal infections: fluconazole (FLC), itraconazole (ITC), voriconazole (VCZ), posaconazole (PCZ), and isavuconazole (IVU) [4,5]
The first crystal structures of full-length heterologous expressed recombinant fungal sterol 14α-demethylase (SDM) in S. cerevisiae were from S. cerevisiae itself and from C. albicans and C. glabrata
Summary
Because azole drugs are amongst the best-tolerated and most active antifungals, they are often the first line treatment in human and veterinary medicine for many fungal diseases [4,16]. Their popularity and extensive use comes at a cost due to the resultant positive selection pressure for azole-resistance amongst fungal pathogens of plants, animals, and humans [17]. This review will focus on key AA substitutions associated with the ligand-binding pocket of SDMs. We will summarize the known impact of these residues on resistance to short- and long-tailed azoles in pathogenic fungi of humans, animals, and plants
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