Salmonella serovars are leading causes of gastrointestinal disease and have become increasingly resistant to fluoroquinolone and cephalosporin antibiotics. Overcoming this healthcare crisis requires new approaches in antibiotic discovery and the identification of unique bacterial targets. In this work, we describe a chemical genomics approach to identify inhibitors of Salmonella virulence. From a cell-based, promoter reporter screen of ∼50,000 small molecules, we identified dephostatin as a non-antibiotic compound that inhibits intracellular virulence factors and polymyxin resistance genes. Dephostatin disrupts signaling through both the SsrA-SsrB and PmrB-PmrA two-component regulatory systems and restores sensitivity to the last-resort antibiotic, colistin. Cell-based experiments and mouse models of infection demonstrate that dephostatin attenuates Salmonella virulence in vitro and in vivo, suggesting that perturbing regulatory networks is a promising strategy for the development of anti-infectives.

沙门氏菌血清是胃肠道疾病的主要原因，对氟喹诺酮和头孢菌素抗生素的耐药性也越来越高。克服这种医疗危机需要在抗生素发现和识别独特细菌靶标方面采取新方法。在这项工作中，我们描述了一种化学基因组学方法来鉴定沙门氏菌的抑制剂毒力。通过对约50,000个小分子的基于细胞的启动子报道分子筛选，我们确定了去磷酸他汀是一种抑制细胞内毒力因子和多粘菌素抗性基因的非抗生素化合物。去磷酸他汀通过SsrA-SsrB和PmrB-PmrA两组分调节系统破坏信号传导，并恢复对最后一种抗生素大肠菌素的敏感性。基于细胞的实验和感染的小鼠模型表明，去氧他汀在体外和体内均可减弱沙门氏菌的毒力，这表明干扰调节网络是开发抗感染药的有希望的策略。