Synthetic Simplification of Carolacton Enables Chemical Genetic Studies in Streptococcus mutans
Synthetic Simplification of Carolacton Enables Chemical Genetic Studies in Streptococcus mutans
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DOI：
10.1021/acsinfecdis.9b00213
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发表时间：
2019-08-01
影响因子：
5.3
通讯作者：
Wuest, William M.
中科院分区：
文献类型：
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作者：
Solinski, Amy E.;Scharnow, Amber M.;Wuest, William M.
在过去的十年里，人们一直在研究大内酯这种天然产物对生物的广泛影响。多项研究表明与调节系统、耐酸机制、生物膜形成以及最近的叶酸脱氢酶（FolD）有关。由于carolacton处理的细胞的低通量分析，阐明变形链球菌生物膜特异性活性的原因的进展受到限制。我们揭示了一种简化的卡罗尔顿启发类似物的发现，该类似物显示了对变形链球菌生物膜细胞的抑制活性。这一发现为突变链球菌的化学遗传筛选提供了概念证明，并确定了碳分解代谢蛋白a信号通路作为假定的靶点。
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 Streptococcus mutans 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 S. mutans biofilm cells. This discovery permitted a proof of concept chemical genetic screen of S. mutans mutants identifying the carbon catabolite protein A signaling pathway as a putative target.