老药新用——洛哌丁胺对胞内病原菌感染的治疗作用

刘洪涛, 李思琦, 邓乐, 史真旭, 姜晨晓, 舒婧妍, 刘源, 邓旭明, 王建锋, 郭志敏, 邱家章

工程（英文） ›› 2024, Vol. 39 ›› Issue (8) : 180-193.

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工程（英文） ›› 2024, Vol. 39 ›› Issue (8) : 180-193. DOI: 10.1016/j.eng.2024.01.011
研究论文
Article

老药新用——洛哌丁胺对胞内病原菌感染的治疗作用

作者信息 +

Repurposing Loperamide as an Anti-Infection Drug for the Treatment of Intracellular Bacterial Pathogens

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History +

摘要

多数抗生素对细胞膜的渗透性较低，且极易在细胞内被降解，导致抗生素在细胞内难以达到有效杀菌浓度，加之耐药菌株的出现和快速传播，使得胞内菌感染的治疗面临巨大挑战。病原菌与宿主细胞相互作用机制的阐明促进了宿主导向疗法（host-directed therapy, HDT）的快速发展。HDT已发展成为最具潜力的抗胞内菌感染的方法之一。基于此，本研究采用庆大霉素保护试验从FDA批准的药物库中筛选能够抑制鼠伤寒沙门氏菌（Salmonella Typhimurium, ST）胞内增殖的药物，发现洛哌丁胺（Loperamide, LPD）可显著抑制ST的胞内增殖。机制研究结果表明LPD处理可促进感染细胞发生自噬并增强其溶酶体活性。进一步研究发现高表达的非转移性黑色素瘤糖蛋白B（glycoprotein nonmetastatic melanoma protein B, GPNMB）介导了LPD诱导的细胞自噬和对胞内菌的清除。动物实验结果表明LPD治疗可显著提升ST感染的大蜡螟幼虫和小鼠模型的存活率、降低感染小鼠靶器官的菌落定殖、缓解ST感染所致的病理损伤。综上所述，本研究为基于HDT策略抗感染药物的开发提供了一种作用机制明确的先导化合物。

Abstract

Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells. The rapid development and dissemination of antimicrobial-resistant strains have exacerbated this dilemma. With the increasing knowledge of host-pathogen interactions, especially bacterial strategies for survival and proliferation within host cells, host-directed therapy (HDT) has attracted increased interest and has emerged as a promising anti-infection method for treating intracellular infection. Herein, we applied a cell-based screening approach to a US Food and Drug Administration (FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium (S. Typhimurium). This screening allowed us to identify the antidiarrheal agent loperamide (LPD) as a potent inhibitor of S. Typhimurium intracellular proliferation. LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity. A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B (GPNMB) induced by LPD. In addition, LPD treatment effectively protected against S. Typhimurium infection in Galleria mellonella and mouse models. Thus, our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens. Moreover, LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.

关键词

胞内菌 / FDA药物 / 老药新用 / 洛哌丁胺 / 自噬 / 非转移性黑色素瘤糖蛋白B /

Keywords

Intracellular bacteria / US Food and Drug Administration (FDA)-approved drugs / Drug repurposing / Loperamide / Autophagy / Glycoprotein nonmetastatic melanoma / protein B

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刘洪涛, 李思琦, 邓乐. 洛哌丁胺对胞内病原菌感染的治疗作用. Engineering. 2024, 39(8): 180-193 https://doi.org/10.1016/j.eng.2024.01.011

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