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Large-Scale Identification of Multiple Classes of Host Defense Peptide-Inducing Compounds for Antimicrobial Therapy

文献类型： 外文期刊

作者： Lyu, Wentao 1 ; Mi, Dehui 3 ; Vinson, Paige N. 3 ; Xiao, Yingping 1 ; Zhang, Guolong 2 ;

作者机构： 1.Zhejiang Acad Agr Sci, Inst Agroprod Safety & Nutr, State Key Lab Managing Biot & Chem Threats Qual &, Hangzhou 310021, Peoples R China

2.Oklahoma State Univ, Dept Anim & Food Sci, Stillwater, OK 74078 USA

3.Vanderbilt Inst Chem Biol, Vanderbilt High Throughput Screening Facil, Nashville, TN 37232 USA

4.Southern Res, High Throughput Screening Facil, Birmingham, AL 35205 USA

关键词： host defense peptides; high-throughput screening; host defense peptide inducers; mocetinostat; antimicrobial resistance

期刊名称：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES （ 影响因子：6.208； 五年影响因子：6.628 ）

ISSN：

年卷期： 2022 年 23 卷 15 期

页码：

收录情况： SCI

摘要： 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.

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