Traditionally, treatments for bacterial infection have focused on killing the microbe or preventing its growth. As antimicrobial resistance becomes more ubiquitous, attention has begun to shift toward disrupting the host-pathogen interaction by improving the host defense. Using a high-throughput, fragment-based screen to identify compounds that alleviate Pseudomonas aeruginosa-mediated killing of Caenorhabditis elegans, we identified over 20 compounds that stimulated host defense gene expression. Five of these molecules were selected for further characterization. Four compounds showed little toxicity against mammalian cells or worms, consistent with their identification in a phenotypic, high-content screen. Each of the compounds activated several host defense pathways, but the pathways were generally dispensable for compound-mediated rescue in Liquid Killing, suggesting redundancy or that the activation of one or more unknown pathways may be driving compound effects. A genetic mechanism was identified for LK56, which required the Mediator subunit MDT-15/MED15 and NHR-49/HNF4 for its function. Interestingly, LK32, LK34, LK38, and LK56 also rescue C. elegans from P. aeruginosa in an agar-based assay, which uses different virulence factors and defense mechanisms. Rescue in an agar-based assay for LK38 entirely depended upon the PMK-1/p38 MAPK pathway. Three compounds, LK32, LK34, and LK56 also conferred resistance to Enterococcus faecalis, and the two lattermost, LK34 and LK56, also reduced pathogenesis from Staphylococcus aureus. This study supports a growing role for MDT-15 and NHR-49 in immune response and identifies 5 molecules that with significant potential for use as tools in the investigation of innate immunity.

中文翻译：

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新型免疫调节剂增强秀丽隐杆线虫对多种病原体的抗性

传统上，细菌感染的治疗方法侧重于杀死微生物或阻止其生长。随着抗菌药物耐药性的日益普及，人们的注意力开始转向通过改善宿主防御能力来破坏宿主与病原体的相互作用。使用基于片段的高通量筛选方法，鉴定减轻铜绿假单胞菌介导的秀丽隐杆线虫致死的化合物，我们鉴定了20多种刺激宿主防御基因表达的化合物。这些分子中的五个被选择用于进一步表征。四种化合物对哺乳动物细胞或蠕虫几乎没有毒性，这与它们在表型，高含量筛选中的鉴定一致。每种化合物都激活了几种宿主防御途径，但这些途径通常在Liquid Killing中对于化合物介导的抢救而言是必不可少的，表明存在冗余或一种或多种未知途径的激活可能正在推动化合物作用。已确定LK56的遗传机制，其功能需要介体亚基MDT-15 / MED15和NHR-49 / HNF4。有趣的是，LK32，LK34，LK38和LK56还可以在琼脂基测定中从铜绿假单胞菌中拯救秀丽隐杆线虫，该方法使用了不同的毒力因子和防御机制。在基于琼脂的LK38分析中的拯救完全取决于PMK-1 / p38 MAPK途径。三种化合物LK32，LK34和LK56也赋予了对粪肠球菌的抗性，而后两种化合物LK34和LK56也减少了金黄色葡萄球菌的发病机理。