Large-Scale Identification of Multiple Classes of Host Defense Peptide-Inducing Compounds for Antimicrobial Therapy.
Large-Scale Identification of Multiple Classes of Host Defense Peptide-Inducing Compounds for Antimicrobial Therapy.
复制标题
DOI：
10.3390/ijms23158400
复制
发表时间：
2022-07-29
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
抗生素耐药性的迅速出现要求采用不太可能产生耐药性的新的抗微生物策略。增加内源性宿主防御肽（hdp）的合成已被证明是一种有效的针对宿主的治疗方法。本研究旨在寻找具有较强诱导内源性HDP合成能力的小分子化合物，以进一步开发新型抗菌药物。通过使用稳定的HDP启动子驱动的荧光素酶报告细胞系HTC/AvBD9-luc，我们对5002种天然和合成化合物进行了高通量筛选，鉴定出110个命中值，最低z分数为2.0。尽管它们在结构和功能上各不相同，但其中一半是I类组蛋白去乙酰化酶、磷酸肌肽3-激酶途径、离子通道、多巴胺和血清素受体的抑制剂。进一步的验证表明，苯甲酰胺组蛋白去乙酰化酶抑制剂moceinostat在鸡巨噬细胞细胞系和空肠外植体中对多种HDP基因的表达有很强的增强作用。重要的是，莫替司他在促进鸡巨噬细胞HDP基因表达和抗菌活性方面比两种结构类似物恩替司他和tucidinostat更有效。综上所述，moceinostat具有增强宿主细胞HDP合成和抗菌活性的能力，可能被开发为一种用于疾病控制和预防的新型抗菌药物。
The rapid emergence of antibiotic resistance demands new antimicrobial strategies that are less likely to develop resistance. Augmenting the synthesis of endogenous host defense peptides (HDPs) has been proven to be an effective host-directed therapeutic approach. This study aimed to identify small-molecule compounds with a strong ability to induce endogenous HDP synthesis for further development as novel antimicrobial agents. By employing a stable HDP promoter-driven luciferase reporter cell line known as HTC/AvBD9-luc, we performed high-throughput screening of 5002 natural and synthetic compounds and identified 110 hits with a minimum Z-score of 2.0. Although they were structurally and functionally diverse, half of these hits were inhibitors of class I histone deacetylases, the phosphoinositide 3-kinase pathway, ion channels, and dopamine and serotonin receptors. Further validations revealed mocetinostat, a benzamide histone deacetylase inhibitor, to be highly potent in enhancing the expression of multiple HDP genes in chicken macrophage cell lines and jejunal explants. Importantly, mocetinostat was more efficient than entinostat and tucidinostat, two structural analogs, in promoting HDP gene expression and the antibacterial activity of chicken macrophages. Taken together, mocetinostat, with its ability to enhance HDP synthesis and the antibacterial activity of host cells, could be potentially developed as a novel antimicrobial for disease control and prevention.
登录
查看更多内容
影响因子：
5.6
作者：
Albanese A;Daly LA;Mennerich D;Kietzmann T;Sée V
通讯作者：
Sée V
对复发或难治性淋巴瘤中的组蛋白脱乙酰基酶抑制剂的2阶段研究。
影响因子：
6.5
作者：
Batlevi CL;Crump M;Andreadis C;Rizzieri D;Assouline SE;Fox S;van der Jagt RHC;Copeland A;Potvin D;Chao R;Younes A
通讯作者：
Younes A
影响因子：
7.3
作者：
Ho, Terence C. S.;Chan, Alex H. Y.;Ganesan, A.
通讯作者：
Ganesan, A.
影响因子：
5.4
作者：
Bommineni, Yugendar R.;Dai, Huaien;Zhang, Guolong
通讯作者：
Zhang, Guolong
DOI：
10.1083/jcb.200812060
发表时间：
2009-06-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee JL;Wang MJ;Chen JY
通讯作者：
Chen JY