Coordinated Regulation of Membrane Homeostasis and Drug Accumulation by Novel Kinase STK-17 in Response to Antifungal Azole Treatment

Hu, Chengcheng; Zhou, Mi; Cao, Xianhe; Xue, Wei; Zhang, Zhenying; Li, Shaojie; Sun, Xiepeng

doi:10.1128/spectrum.00127-22

Cited by 2 publications

(1 citation statement)

References 63 publications

(112 reference statements)

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“…Azoles are the structural core of the most popular drugs used for the treatment of various diseases. Interest in organophosphorus compounds, including those containing azolyl moieties, increases every year due to their high and unusual (specific) biological activity [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. In recent years, in connection with the rapid development of experimental technology, previously very problematic studies that are of key importance for the stereochemistry of heterocycles have become rather more possible and routine.…”

Section: Discussionmentioning

confidence: 99%

Organophosphorus Azoles Incorporating a Tetra-, Penta-, and Hexacoordinated Phosphorus Atom: NMR Spectroscopy and Quantum Chemistry

Ларина

2023

Molecules

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The review presents extensive data (from the author’s work and the literature) on the stereochemical structure of functionalized organophosphorus azoles (pyrroles, pyrazoles, imidazoles and benzazoles) and related compounds, using multinuclear 1Н, 13С, 31Р NMR spectroscopy and quantum chemistry. 31P NMR spectroscopy, combined with high-level quantum-chemical calculations, is the most convenient and reliable approach to studying tetra-, penta-, and hexacoordinated phosphorus atoms of phosphorylated N-vinylazoles and evaluating their Z/E isomerization.

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Section: Discussionmentioning

confidence: 99%

Organophosphorus Azoles Incorporating a Tetra-, Penta-, and Hexacoordinated Phosphorus Atom: NMR Spectroscopy and Quantum Chemistry

Ларина

2023

Molecules

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PWWP domain-containing protein Crf4-3 specifically modulates fungal azole susceptibility by regulating sterol C-14 demethylase ERG11

Yu,

Ye,

Zhou

et al. 2024

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The widespread use of azole antifungals in agriculture and clinical settings has led to serious drug resistance. Overexpression of the azole drug target 14α-demethylase ERG11 (CYP51) is the most common fungal resistance mechanism. However, the presence of additional regulatory proteins in the transcriptional response of erg11 is not yet fully elucidated. In this study, leveraging the identified key promoter region of erg11 that controls its response to azoles in Neurospora crassa , we pinpointed a protein, Crf4-3, which harbors a PWWP domain and exerts a positive regulatory influence on azole resistance, as determined by DNA pulldown assays. The removal of Crf4-3 results in heightened sensitivity to azoles while remaining unaffected by other stressors tested. Additionally, the deletion leads to the abolition of transcriptional responses of genes such as erg11 and erg6 to ketoconazole. Interestingly, the basal expression of erg1 , erg11 , erg25 , and erg3A is also affected by the deletion of crf4-3 , indicating its role in sterol homeostasis. Crf4-3 homologs are broadly distributed across the Pezizomycotina fungi. The gene deletion for its homologous protein in Aspergillus fumigatus also significantly improves sensitivity to azoles such as voriconazole, primarily through the attenuation of the transcriptional response of erg11 . Our data, for the first time, identified Crf4-3 as a novel regulatory protein in the azole stress response of filamentous fungi, offering fresh insights into the mechanisms of azole resistance. IMPORTANCE Transcriptional control of pivotal genes, such as erg11 , stands as the primary driver of azole resistance. Although considerable effort has been dedicated to identifying transcription factors involved, our knowledge regarding the use of transcriptional regulation strategies to combat azole resistance is currently limited. In this study, we reveal that a PWWP domain-containing protein Crf4-3, which is conserved in Pezizomycotina fungi, modulates fungal azole sensitivity by transcriptionally regulating sterol biosynthetic genes, including erg11 . These results also broaden the understanding of fungal PWWP domain-containing proteins regarding their roles in regulating resistance against azole antifungals. Considering research on small molecules targeting the PWWP domain in humans, Crf4-3 homolog emerges as a promising target for designing fungal-specific drugs to combat azole resistance.

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Coordinated Regulation of Membrane Homeostasis and Drug Accumulation by Novel Kinase STK-17 in Response to Antifungal Azole Treatment

Cited by 2 publications

References 63 publications

Organophosphorus Azoles Incorporating a Tetra-, Penta-, and Hexacoordinated Phosphorus Atom: NMR Spectroscopy and Quantum Chemistry

Organophosphorus Azoles Incorporating a Tetra-, Penta-, and Hexacoordinated Phosphorus Atom: NMR Spectroscopy and Quantum Chemistry

PWWP domain-containing protein Crf4-3 specifically modulates fungal azole susceptibility by regulating sterol C-14 demethylase ERG11

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