Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens

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.

Point mutations in the squalene epoxidase erg1 and sterol 14‐α demethylase erg11 gene of T indotineae isolates indicate that the resistant mutant strains evolved independently

“…Related genes are present in species of most kingdoms including fungi, bacteria, plants and animals 13 . Point mutations of this class of genes result in amino acid changes in specific positions, which convey resistance to specific azoles 13,14 . Erg11/Cyp51 point mutation isolates that confer azoles resistance, have evolved in nearly all human pathogenic fungi like the Ascomycota genera Candida and Aspergillus or basidiomycota genera Cryptococcus and explain the intrinsic resistance of mucoromycota genera Mucor and Rhizopus 14 .…”

“…Point mutations of this class of genes result in amino acid changes in specific positions, which convey resistance to specific azoles 13,14 . Erg11/Cyp51 point mutation isolates that confer azoles resistance, have evolved in nearly all human pathogenic fungi like the Ascomycota genera Candida and Aspergillus or basidiomycota genera Cryptococcus and explain the intrinsic resistance of mucoromycota genera Mucor and Rhizopus 14 . Erg11 resistance mechanisms show remarkable resemblance, although, the fungi belong to different phyla 13,14 .…”

“…Erg11/Cyp51 point mutation isolates that confer azoles resistance, have evolved in nearly all human pathogenic fungi like the Ascomycota genera Candida and Aspergillus or basidiomycota genera Cryptococcus and explain the intrinsic resistance of mucoromycota genera Mucor and Rhizopus 14 . Erg11 resistance mechanisms show remarkable resemblance, although, the fungi belong to different phyla 13,14 . Azole belong to broad class of substance with several length of side chains like short‐tailed fluconazole or voriconazole or long‐tailed itraconazole for example.…”

“…Azole belong to broad class of substance with several length of side chains like short‐tailed fluconazole or voriconazole or long‐tailed itraconazole for example. Binding of azoles with specific Erg11 amino acid positions depends also of the chemical nature of azole subclasses and different amino acid positions were involved in short‐tailed or long‐tailed azoles interactions 14 . Unfortunately, information on this type of resistance is sparse for Trichophyton or other Arthrodermataceae so far and, therefore, Aspergillus as phylogenetically related fungal genera has to act as the model organism.…”

Structural Insights into the Azole Resistance of the Candida albicans Darlington Strain Using Saccharomyces cerevisiae Lanosterol 14α-Demethylase as a Surrogate

“…A common and clinically relevant mutation in C. albicans lanosterol 14α-demethylase (CaLDM) confers resistance to FLC and voriconazole (VCZ) by substituting the tyrosine at position 132 within the substrate binding site with phenylalanine (Y132F) or histidine (Y132H) [22][23][24][25][26][27][28][29][30][31]. Homologous mutations are found in the ERG11 genes of other fungal pathogens of humans and plants [2,3,32]. Compared with single site mutations, multisite mutations in LDM can significantly increase FLC resistance [21].…”