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 U.S. Food and Drug Administration (FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Typhimurium ( Typhimurium). This screening allowed us to identify the antidiarrheal agent loperamide (LPD) as a potent inhibitor of 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 Typhimurium infection in 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.

中文翻译：

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将洛哌丁胺重新用作治疗细胞内细菌病原体的抗感染药物

由细胞内细菌病原体引起的感染很难治疗，因为大多数抗生素的细胞渗透性较低并且在细胞内快速降解。抗菌药物耐药菌株的快速发展和传播加剧了这一困境。随着对宿主与病原体相互作用的了解不断增加，特别是对宿主细胞内细菌生存和增殖策略的了解，宿主定向治疗（HDT）引起了越来越多的兴趣，并已成为一种有前途的治疗细胞内感染的抗感染方法。在此，我们将基于细胞的筛选方法应用于美国食品和药物管理局（FDA）批准的药物库，以鉴定可以抑制鼠伤寒菌（Typhimurium）细胞内复制的化合物。这次筛选使我们能够确定止泻剂洛哌丁胺 (LPD) 是鼠伤寒杆菌细胞内增殖的有效抑制剂。LPD处理感染细胞显着促进宿主自噬反应和溶酶体活性。一项机制研究表明，宿主自噬的增加和细胞内细菌的消除依赖于 LPD 诱导的糖蛋白非转移性黑色素瘤蛋白 B (GPNMB) 的高表达。此外，LPD 治疗可有效防止小鼠模型中的鼠伤寒感染。因此，我们的研究表明 LPD 可能有助于治疗由细胞内细菌病原体引起的疾病。此外，LPD可能作为基于HDT策略开发抗感染药物的有前途的先导化合物。