Characterization of an allosteric inhibitor of fungal-specific C-24 sterol methyltransferase to treat Candida albicans infections

Jin, Xueyang; Hou, Xuben; Wang, Xue; Zhang, Ming; Chen, Jinyao; Song, Minghui; Zhang, Jiaozhen; Zheng, Hongbo; Chang, Wenqiang; Lou, Hongxiang

doi:10.1016/j.chembiol.2023.04.010

Cited by 8 publications

(21 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accordingly, the downstream hyphal-specific genes, such as ECE1 , ALS3 , and HWP1 , were downregulated (Figure E). These results indicate that d28 inhibits hyphal growth by modulating the Ras1-cAMP-PKA pathway, Nrg1, and Ume6, similar to the previously reported antifungal mechanism of H55 …”

Section: Results and Discussionsupporting

confidence: 89%

“…We found that d28 treatment efficiently protected the Erg6 protein from temperature-dependent degradation (Figure C,D), suggesting that Erg6 remains the target of d28 . Furthermore, we examined whether d28 shared the mode of action of H55 , which modulates the Ras1-cAMP-PKA signaling pathway, transcriptional regulators Nrg1 and Ume6 by inhibiting Erg6 . The classical Ras1-cAMP-PKA signaling pathway regulates hyphal growth under multiple hyphal-inducing conditions .…”

Section: Results and Discussionmentioning

confidence: 99%

“…Hyphal forms typically express higher adhesin levels than yeast forms . The adhesion assay showed that compound d28 significantly reduced the adhesion of C.…”

Section: Results and Discussionmentioning

confidence: 99%

“…The binding poses of H55 and d28 within the protein were investigated by performing induced-fit docking (Schrödinger suite, Release 2022-2) following the standard protocol and 20 docking poses were generated per ligand. The binding pocket that we had previously used for the Erg6- H55 complex model was selected as the binding position . The other parameters were set as the default.…”

Section: Methodsmentioning

confidence: 99%

“…The sterols were extracted in 20 mL of petroleum ether and vaporized. GC–MS analyses were conducted, as previously described …”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

Structure-Based Optimization of Novel Sterol 24-C-Methyltransferase Inhibitors for the Treatment of Candida albicans Infections

Wang,

Jin,

Zhao

et al. 2024

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Interfering with sterol biosynthesis is an important strategy for developing safe and effective antifungal drugs. We previously identified compound H55 as an allosteric inhibitor of the fungal-specific C-24 sterol methyltransferase Erg6 for treating Candida albicans infections. Herein, 62 derivatives of H55 were designed and synthesized based on target−ligand interactions to identify more active candidates. Among them, d28 displayed the most potent antivirulence ability (MHIC 50 = 0.25 μg/mL) by targeting Erg6, exhibiting an 8-fold increase in potency compared with H55. Moreover, d28 significantly outperformed H55 in inhibiting cell adhesion and biofilm formation, and exhibited minimal cytotoxicity and negligible potential to induce drug resistance. Of note, the coadministration of d28 and other sterol biosynthesis inhibitors, such as tridemorph or terbinafine, demonstrated a strong synergistic antifungal action in vitro and in vivo in a murine skin infection model. These results support the potential application of d28 in the treatment of C. albicans infections.

show abstract

Section: Results and Discussionsupporting

confidence: 89%

Section: Results and Discussionmentioning

confidence: 99%

“…Hyphal forms typically express higher adhesin levels than yeast forms . The adhesion assay showed that compound d28 significantly reduced the adhesion of C.…”

Section: Results and Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The sterols were extracted in 20 mL of petroleum ether and vaporized. GC–MS analyses were conducted, as previously described …”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations