Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
Veterans Administration Medical Center, Northport, New York, USA.
Antimicrob Agents Chemother. 2018 Apr 26;62(5). doi: 10.1128/AAC.00156-18. Print 2018 May.
The incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active against and had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.
近年来，侵袭性真菌感染的发病率急剧上升。目前的抗真菌药物要么有毒性，可能与其他药物相互作用，要么活性谱狭窄，要么诱导真菌耐药性。因此，非常需要新的抗真菌药物，其作用机制可能是新颖的。此前，我们的研究小组报道了一种叫做 BHBM 的酰腙，它靶向鞘脂代谢途径，对几种真菌具有很强的抗真菌活性。在这项研究中，我们筛选了 19 种 BHBM 的衍生物。其中 3 种衍生物对具有很高的活性，对哺乳动物细胞的毒性较低。特别是其中一种叫做 D13 的衍生物具有很高的选择性指数，在隐球菌病、念珠菌病和肺曲霉病的动物模型中表现出更好的活性。D13 还表现出合适的药代动力学特性，并能够穿透血脑屏障。这些结果表明酰腙是研究和开发新型抗真菌药物的有前途的分子。
