A macrophage-based screen identifies antibacterial compounds selective for intracellular Salmonella Typhimurium
A macrophage-based screen identifies antibacterial compounds selective for intracellular Salmonella Typhimurium
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DOI：
10.1038/s41467-018-08190-x
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发表时间：
2019-01-14
影响因子：
16.6
通讯作者：
Brown, Eric D.
中科院分区：
文献类型：
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作者：
Ellis, Michael J.;Tsai, Caressa N.;Brown, Eric D.
鼠伤寒沙门菌（Salmonella Typhimurium， S. Tm）通过逃避固有免疫反应并在宿主吞噬细胞内复制，在易感宿主中建立全身性感染。在这里，我们试图通过平行化学筛选来识别细胞内S. Tm复制的抑制剂，以抑制在巨噬细胞模拟培养基和巨噬细胞内生长的S. Tm。我们确定了几种化合物，抑制沙门氏菌生长在细胞内环境和酸性，离子限制的媒体。我们报道了精神活性药物美特高林的抗菌活性，这是对细胞内S. Tm特异性。在麦高林存在下筛选S. Tm缺失文库显示外膜突变体对麦高林活性的超敏性。美特高碱破坏细菌细胞质膜的质子动力，延长动物在系统性链球菌感染期间的存活时间。这项工作强调了细胞内筛选对体内功效的预测性质，并确定了美高梅碱作为一种新的抗沙门氏菌活性物质。
Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella.