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

老药新用——洛哌丁胺对胞内病原菌感染的治疗作用

作　　者：Hongtao Liu Siqi Li Le Deng Zhenxu Shi Chenxiao Jiang Jingyan Shu Yuan Liu Xuming Deng Jianfeng Wang Zhimin Guo Jiazhang Qiu 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

机构地区：[1]State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases&Key Laboratory of Zoonosis Research,Ministry of Education,Institute of Zoonosis,College of Veterinary Medicine&Jilin University,Changchun 130062,China [2]Center for Pathogen Biology and Infectious Diseases,The First Hospital of Jilin University,Changchun 130031,China [3]Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses,Institute of Comparative Medicine,College of Veterinary Medicine,Yangzhou University,Yangzhou 225009,China

出　　处：《Engineering》2024年第8期180-193,共14页工程（英文）

基　　金：supported by the National Key Research and Development Program of China(2021YFD1801000);the Natural Science Foundation of China(32373066);the Natural Science Foundation of Jilin Province(20230101142JC);the Fundamental Research Funds for the Central Universities.

摘　　要：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 antiinfection 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：Intracellular bacteria US Food and Drug Administration(FDA)-approved drugs Drug repurposing LOPERAMIDE AUTOPHAGY Glycoprotein nonmetastatic melanoma protein B 

分 类 号：R978[医药卫生—药品]