尿路感染(UTI)是主要的全球健康问题,并且主要由泌尿致病性大肠杆菌(UPEC)引起。尿路感染是处方抗菌药物使用的主要原因。UPEC和其他尿路病原体中抗菌素耐药性的不断增加对当前的治疗实践构成了严重威胁。铜是营养免疫的效应物,其在感染期间阻碍病原体的生长。我们假设铜会增加选择的小分子对细菌病原体的毒性。我们用51,098个分子的文库进行了小分子筛选活动,以检测以铜依赖性方式抑制UPECΔtolC突变体的命中。一个分子,表示为大肠杆菌抑制剂或ECIN,被鉴定为野生型UPEC菌株的铜响应抑制剂。我们的基因表达和金属含量分析结果表明,ECIN与铜协同工作,加剧了UPEC中的铜毒性。ECIN具有针对医学和兽医学意义的病原体的广谱活性,包括鲍曼不动杆菌,铜绿假单胞菌,和耐甲氧西林金黄色葡萄球菌。亚抑制水平的ECIN消除UPEC生物膜形成。用ECIN处理的UPEC的转录组分析揭示了多种应激反应系统的诱导。此外,我们证明L-半胱氨酸可以挽救暴露于ECIN的UPEC的生长。总之,我们报道了一种新型铜响应性小分子UPEC抑制剂的鉴定和表征。尿路感染(UTI)是一种无处不在的传染病,每年影响数百万人。尿路致病性大肠杆菌(UPEC)是UTI的主要病因。然而,由于UPEC和其他尿路病原体中增加的抗微生物剂抗性,UTI变得越来越难以用抗微生物剂解决。这里,我们报道了一种新型铜响应性小分子UPEC抑制剂的鉴定和表征。除了大肠杆菌,这种小分子还抑制具有医学和兽医学意义的病原体,包括鲍曼不动杆菌,铜绿假单胞菌,和耐甲氧西林金黄色葡萄球菌。
Urinary tract infections (UTIs) are a major global health problem and are caused predominantly by uropathogenic Escherichia coli (
UPEC). UTIs are a leading cause of prescription antimicrobial use. Incessant increase in antimicrobial resistance in
UPEC and other uropathogens poses a serious threat to the current treatment practices. Copper is an effector of nutritional immunity that impedes the growth of pathogens during infection. We hypothesized that copper would augment the toxicity of select small molecules against bacterial pathogens. We conducted a small molecule screening campaign with a library of 51,098 molecules to detect hits that inhibit a UPEC ΔtolC mutant in a copper-dependent manner. A molecule, denoted as E. coli inhibitor or ECIN, was identified as a copper-responsive inhibitor of wild-type UPEC strains. Our gene expression and metal content analysis results demonstrate that ECIN works in concert with copper to exacerbate Cu toxicity in UPEC. ECIN has a broad spectrum of activity against pathogens of medical and veterinary significance including Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. Subinhibitory levels of ECIN eliminate
UPEC biofilm formation. Transcriptome analysis of UPEC treated with ECIN reveals induction of multiple stress response systems. Furthermore, we demonstrate that L-cysteine rescues the growth of
UPEC exposed to ECIN. In summary, we report the identification and characterization of a novel copper-responsive small molecule inhibitor of UPEC.IMPORTANCEUrinary tract infection (UTI) is a ubiquitous infectious condition affecting millions of people annually. Uropathogenic Escherichia coli (
UPEC) is the predominant etiological agent of UTI. However, UTIs are becoming increasingly difficult to resolve with antimicrobials due to increased antimicrobial resistance in UPEC and other uropathogens. Here, we report the identification and characterization of a novel copper-responsive small molecule inhibitor of UPEC. In addition to E. coli, this small molecule also inhibits pathogens of medical and veterinary significance including Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus.