Solinski Amy E, Scharnow Amber M, Fraboni Americo J, Wuest William M
Department of Chemistry , Emory University , 1515 Dickey Drive , Atlanta , Georgia 30322 , United States.
Emory Antibiotic Resistance Center , Emory University School of Medicine , 201 Dowman Drive , Atlanta , Georgia 30322 , United States.
ACS Infect Dis. 2019 Aug 9;5(8):1480-1486. doi: 10.1021/acsinfecdis.9b00213. Epub 2019 Jun 25.
Understanding the broader biological impact of carolacton, a macrolactone natural product, has been ongoing for the past decade. Multiple studies have shown connections to regulatory systems, acid tolerance mechanisms, biofilm formation, and recently folate dehydrogenase (FolD). Progress elucidating the cause of biofilm-specific activity in has been limited due to low-throughput analyses of carolacton-treated cells. We disclose the discovery of a simplified carolacton-inspired analog that demonstrates inhibitory activity against biofilm cells. This discovery permitted a proof of concept chemical genetic screen of mutants identifying the carbon catabolite protein A signaling pathway as a putative target.
在过去十年中，人们一直在研究大环内酯类天然产物卡罗内酯更广泛的生物学影响。多项研究表明，它与调节系统、耐酸机制、生物膜形成以及最近发现的叶酸脱氢酶（FolD）存在关联。由于对卡罗内酯处理过的细胞进行低通量分析，阐明其生物膜特异性活性原因的进展有限。我们公布了一种简化的受卡罗内酯启发的类似物的发现，该类似物对生物膜细胞具有抑制活性。这一发现使得对突变体进行概念验证化学遗传筛选成为可能，从而确定碳分解代谢物蛋白A信号通路为一个假定靶点。
