Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens
| Autor: | Rosam, Katharina, Monk, Brian C., Lackner, Michaela |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
therapy
treatment cytochrome P450 point mutations cross-kingdom pathogens pan-fungal kingdom mutation azole drugs Review ergosterol biosynthesis antifungal resistance heme-containing active site water-mediated hydrogen bond network imidazole substrate entry channel sterol 14α-demethylase triazole lanosterol 14α-demethylase tandem repeat lcsh:Biology (General) prophylaxis promotor region lcsh:QH301-705.5 amino acid substitution azole agrochemicals |
| Zdroj: | Journal of Fungi, Vol 7, Iss 1, p 1 (2021) Journal of Fungi |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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