Fungal Lanosterol 14α-demethylase: A target for next-generation antifungal design

Monk, Brian C.; Sagatova, A.; Hosseini, Parham; Ruma, Yasmeen N.; Wilson, R.K.; Keniya, M.V.

doi:10.1016/j.bbapap.2019.02.008

Cited by 83 publications

(63 citation statements)

References 214 publications

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“…Azole antifungals tend to be fungistatic rather than fungicidal. This property provides fungi opportunity to adapt to this antifungal class [22,23]. Long-term use, repeated use, overuse and/or under dosing of azole drugs favor the development of azole resistance [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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

Rosam

Monk

Lackner

2020

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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.

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Section: Introductionmentioning

confidence: 99%

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

Rosam

Monk

Lackner

2020

JoF

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“…Ergosterol is a key component of fungal cell membranes and ensures their integrity as well as fluidity. Its biosynthesis involves the 14-α sterol demethylase Cyp51A, which is the primary target of azole-based antifungal drugs such as voriconazole (Odds et al, 2003;Becher & Wirsel, 2012;Monk et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Structural basis of HapE^P88L-linked antifungal triazole resistance in Aspergillus fumigatus

et al. 2020

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Azoles are first-line therapeutics for human and plant fungal infections, but their broad use has promoted the development of resistances. Recently, a pan-azole–resistant clinical Aspergillus fumigatus isolate was identified to carry the mutation P88L in subunit HapE of the CCAAT-binding complex (CBC), a conserved eukaryotic transcription factor. Here, we define the mechanistic basis for resistance in this isolate by showing that the HapEP88L mutation interferes with the CBC’s ability to bend and sense CCAAT motifs. This failure leads to transcriptional derepression of the cyp51A gene, which encodes the target of azoles, the 14-α sterol demethylase Cyp51A, and ultimately causes drug resistance. In addition, we demonstrate that the CBC-associated transcriptional regulator HapX assists cyp51A repression in low-iron environments and that this iron-dependent effect is lost in the HapEP88L mutant. Altogether, these results indicate that the mutation HapEP88L confers increased resistance to azoles compared with wt A. fumigatus, particularly in low-iron clinical niches such as the lung.

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“…The identification of drug-like chemical features and theoretical ligand structures as biologically active hits or leads is easily achievable nowadays due to the availability of high resolution structural analysis techniques such as X-ray crystallography and in silico drug design tools. Both structure-based molecular docking programs and ligand-based molecular modeling studies can be employed for this purpose [5].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Novel 1,3-Thiazole and 2-Hydrazinyl-1,3-Thiazole Derivatives as Anti-Candida Agents: In Vitro Antifungal Screening, Molecular Docking Study, and Spectroscopic Investigation of their Binding Interaction with Bovine Serum Albumin

et al. 2019

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In the context of there being a limited number of clinically approved drugs for the treatment of Candida sp.-based infections, along with the rapid development of resistance to the existing antifungals, two novel series of 4-phenyl-1,3-thiazole and 2-hydrazinyl-4-phenyl-1,3-thiazole derivatives were synthesized and tested in vitro for their anti-Candida potential. Two compounds (7a and 7e) showed promising inhibitory activity against the pathogenic C. albicans strain, exhibiting substantially lower MIC values (7.81 μg/mL and 3.9 μg/mL, respectively) as compared with the reference drug fluconazole (15.62 μg/mL). Their anti-Candida activity is also supported by molecular docking studies, using the fungal lanosterol C14α-demethylase as the target enzyme. The interaction of the most biologically active synthesized compound 7e with bovine serum albumin was investigated through fluorescence spectroscopy, and the obtained data suggested that this molecule might efficiently bind carrier proteins in vivo in order to reach the target site.

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Fungal Lanosterol 14α-demethylase: A target for next-generation antifungal design

Cited by 83 publications

References 214 publications

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

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

Structural basis of HapE^P88L-linked antifungal triazole resistance in Aspergillus fumigatus

Design and Synthesis of Novel 1,3-Thiazole and 2-Hydrazinyl-1,3-Thiazole Derivatives as Anti-Candida Agents: In Vitro Antifungal Screening, Molecular Docking Study, and Spectroscopic Investigation of their Binding Interaction with Bovine Serum Albumin

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Fungal Lanosterol 14α-demethylase: A target for next-generation antifungal design

Cited by 83 publications

References 214 publications

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

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

Structural basis of HapEP88L-linked antifungal triazole resistance in Aspergillus fumigatus

Design and Synthesis of Novel 1,3-Thiazole and 2-Hydrazinyl-1,3-Thiazole Derivatives as Anti-Candida Agents: In Vitro Antifungal Screening, Molecular Docking Study, and Spectroscopic Investigation of their Binding Interaction with Bovine Serum Albumin

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Structural basis of HapE^P88L-linked antifungal triazole resistance in Aspergillus fumigatus