McBrayer Dominic N, Gantman Brooke K, Tal-Gan Yftah
Department of Chemistry , University of Nevada, Reno , 1664 N. Virginia Street , Reno , Nevada 89557 , United States.
ACS Infect Dis. 2019 Jun 14;5(6):1035-1041. doi: 10.1021/acsinfecdis.9b00097. Epub 2019 Apr 19.
The growing prevalence of multiantibiotic-resistant bacteria necessitates looking at potential alternative approaches for attenuating infections by bacteria while reducing the rate of antibiotic resistance development. Enterococcus faecalis is responsible for a large percentage of clinical enterococci infections, and its pathogenicity has been demonstrated to be influenced by quorum sensing (QS). In this study, we report the systematic study of the relationship between backbone hydrogens and the ability to activate the FsrC receptor. We demonstrate that N-methylation was particularly well-tolerated at one site (Phe7) and granted stability against protease digestion, increasing the peptide half-life relative to the native signal by more than 6-fold. The inclusion of the N-Me-Phe7 modification may be useful for improving the pharmacological properties of E. faecalis QS inhibitors as part of the development of future therapeutic candidates.
多重耐药菌的日益流行使得有必要寻找潜在的替代方法来减轻细菌感染，同时降低抗生素耐药性的发展速度。粪肠球菌是临床肠球菌感染的主要致病菌，其致病性已被证明受群体感应（QS）影响。在本研究中，我们报告了对主链氢与激活FsrC受体能力之间关系的系统研究。我们证明，在一个位点（Phe7）进行N-甲基化特别耐受，并赋予了抗蛋白酶消化的稳定性，使肽的半衰期相对于天然信号增加了6倍以上。作为未来治疗候选药物开发的一部分，包含N-Me-Phe7修饰可能有助于改善粪肠球菌QS抑制剂的药理特性。
