Lanosterol 14α-demethylase (CYP51)/histone deacetylase (HDAC) dual inhibitors for treatment of Candida tropicalis and Cryptococcus neoformans infections

Tianbao Zhu; Xi Chen; Chenglan Li; Jie Tu; Na Liu; Defeng Xu; Chunquan Sheng

doi:10.1016/j.ejmech.2021.113524

Lanosterol 14α-demethylase (CYP51)/histone deacetylase (HDAC) dual inhibitors for treatment of Candida tropicalis and Cryptococcus neoformans infections

Eur J Med Chem. 2021 Oct 5:221:113524. doi: 10.1016/j.ejmech.2021.113524. Epub 2021 May 7.

Authors

Tianbao Zhu¹, Xi Chen², Chenglan Li³, Jie Tu³, Na Liu⁴, Defeng Xu⁵, Chunquan Sheng⁶

Affiliations

¹ National & Local Joint Engineering Research Center for High-efficiency Refining and High-quality Utilization of Biomass, School of Pharmacy, 1 Gehu Road, Changzhou University, Changzhou, 213164, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
² Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, 1 Xuefu Avenue, Xi'an, 710127, China.
³ School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
⁴ School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: liuna@smmu.edu.cn.
⁵ National & Local Joint Engineering Research Center for High-efficiency Refining and High-quality Utilization of Biomass, School of Pharmacy, 1 Gehu Road, Changzhou University, Changzhou, 213164, China. Electronic address: markxu@cczu.edu.cn.
⁶ School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: shengcq@smmu.edu.cn.

PMID: 33992927
DOI: 10.1016/j.ejmech.2021.113524

Abstract

Invasive fungal infections remain a challenge due to lack of effective antifungal agents and serious drug resistance. Discovery of antifungal agents with novel antifungal mechanism is important and urgent. Previously, we designed the first CYP51/HDAC dual inhibitors with potent activity against resistant Candida albicans infections. To better understand the antifungal spectrum and synergistic mechanism, herein new CYP51/HDAC dual inhibitors were designed which showed potent in vitro and in vivo antifungal activity against C. neoformans and C. tropicalis infections. Antifungal mechanism studies revealed that the CYP51/HDAC dual inhibitors acted by inhibiting various virulence factors of C. tropicalis and C. neoformans and down-regulating resistance-associated genes. This study highlights the potential of CYP51/HDAC dual inhibitors as a promising strategy for the discovery of novel broad-spectrum antifungal agents.

Keywords: Antifungal; CYP51/HDAC dual Inhibitors; Candida tropicalis; Cryptococcus neoformans; Virulence factors.

MeSH terms

14-alpha Demethylase Inhibitors / chemical synthesis
14-alpha Demethylase Inhibitors / chemistry
14-alpha Demethylase Inhibitors / pharmacology*
Antifungal Agents / chemical synthesis
Antifungal Agents / chemistry
Antifungal Agents / pharmacology*
Candida tropicalis / drug effects
Candida tropicalis / metabolism
Candidiasis, Cutaneous / drug therapy*
Candidiasis, Cutaneous / metabolism
Cryptococcosis / drug therapy*
Cryptococcosis / metabolism
Cryptococcus neoformans / drug effects
Cryptococcus neoformans / metabolism
Cytochrome P450 Family 51 / antagonists & inhibitors
Cytochrome P450 Family 51 / metabolism
Dose-Response Relationship, Drug
Drug Resistance, Fungal / drug effects
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship

Substances

14-alpha Demethylase Inhibitors
Antifungal Agents
Histone Deacetylase Inhibitors
Cytochrome P450 Family 51
Histone Deacetylases