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.
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.
Eur J Med Chem. 2021 Oct 5;221:113524. doi: 10.1016/j.ejmech.2021.113524. Epub 2021 May 7.
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.
由于缺乏有效的抗真菌药物和严重的耐药性，侵袭性真菌感染仍然是一个挑战。发现具有新型抗真菌机制的抗真菌药物是重要且紧迫的。此前，我们设计了首个具有抗耐药白色念珠菌感染活性的 CYP51/HDAC 双重抑制剂。为了更好地了解抗真菌谱和协同作用机制，本文设计了新的 CYP51/HDAC 双重抑制剂，对新型隐球菌和热带念珠菌感染具有强大的体外和体内抗真菌活性。抗真菌机制研究表明，CYP51/HDAC 双重抑制剂通过抑制新型隐球菌和热带念珠菌的各种毒力因子和下调耐药相关基因发挥作用。本研究强调了 CYP51/HDAC 双重抑制剂作为发现新型广谱抗真菌药物的有前途的策略的潜力。
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