Rational Design of Potent Activators and Inhibitors of the Enterococcus faecalis Fsr Quorum Sensing Circuit.
Rational Design of Potent Activators and Inhibitors of the Enterococcus faecalis Fsr Quorum Sensing Circuit.
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DOI：
10.1021/acschembio.8b00610
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发表时间：
2018-09-21
影响因子：
4
通讯作者：
Tal-Gan Y
中科院分区：
文献类型：
--
作者：
McBrayer DN;Cameron CD;Gantman BK;Tal-Gan Y
细菌对常规抗生素的耐药性发展速度越来越快，这就需要确定可能会降低细菌适应能力的替代治疗可能性。粪肠球菌仍然是临床肠球菌感染的主要原因，并表现出群体感应(QS)依赖的致病性。在这里，我们报告了基于大环肽的粪肠球菌FSR QS回路激活剂和抑制剂的研究进展。为此，我们开发、优化和比较了三条含内酯大环肽支架的合成路线。然后，我们利用过去和现在对天然QS信号肽的构效关系(SAR)的见解，合理地设计了迄今为止发现的最有效的FSR QS电路的激活剂和抑制剂。这些多肽的应用可以提供一种方法来减弱粪肠球菌的致病性，而不会对细菌产生明显的选择压力来产生耐药性。
The increasing rate of resistance development to conventional antibiotics by bacteria necessitates the identification of alternative treatment possibilities that can reduce the ability of bacteria to adapt. Enterococcus faecalis remains the leading cause of clinical enterococci infections and has exhibited quorum sensing (QS)-dependent pathogenicity. Here we report the development of macrocyclic peptide-based activators and inhibitors of the E. faecalis Fsr QS circuitry. To this end, we developed, optimized, and compared three synthetic routes for lactone-containing macrocyclic peptide scaffolds. We then utilized previous and current structure-activity relationship (SAR) insights of the native QS signaling peptide to rationally design the most potent activators and inhibitors of the Fsr QS circuitry identified to date. The application of these peptides could provide a means to attenuate the pathogenicity of E. faecalis without introducing significant selective pressure on the bacteria to develop resistance.
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