Koirala Bimal, Hillman Robert A, Tiwold Erin K, Bertucci Michael A, Tal-Gan Yftah
Department of Chemistry, University of Nevada, Reno, 1664 North Virginia Street, Reno, Nevada, 89557, United States.
Department of Chemistry, Moravian College, 1200 Main Street, Bethlehem, Pennsylvania, 18018, United States.
Beilstein J Org Chem. 2018 Jul 16;14:1769-1777. doi: 10.3762/bjoc.14.151. eCollection 2018.
Quorum sensing (QS) is a cell-cell communication mechanism that enables bacteria to assess their population density and alter their behavior upon reaching high cell number. Many bacterial pathogens utilize QS to initiate an attack on their host, thus QS has attracted significant attention as a potential antivirulence alternative to traditional antibiotics. , a notorious human pathogen responsible for a variety of acute and chronic infections, utilizes the competence regulon and its associated signaling peptide, the competence stimulating peptide (CSP), to acquire antibiotic resistance and establish an infection. In this work, we sought to define the binding pockets within the ComD1 receptor used for binding the hydrophobic side-chain residues in CSP1 through the introduction of highly-conservative point mutations within the peptide. Optimization of these binding interactions could lead to the development of highly potent CSP-based QS modulators while the inclusion of non-natural amino acids within the CSP sequence would confer resistance to protease degradation, a requirement for drug candidates.
群体感应（QS）是一种细胞间通讯机制，它使细菌能够评估其种群密度，并在细胞数量达到较高水平时改变其行为。许多细菌病原体利用群体感应来启动对宿主的攻击，因此，作为传统抗生素的一种潜在抗毒力替代品，群体感应已引起了广泛关注。肺炎链球菌是一种臭名昭著的人类病原体，可导致多种急性和慢性感染，它利用感受态调节子及其相关信号肽——感受态刺激肽（CSP）来获得抗生素抗性并建立感染。在这项工作中，我们试图通过在肽段中引入高度保守的点突变来确定ComD1受体中用于结合CSP1中疏水侧链残基的结合口袋。优化这些结合相互作用可能会导致开发出高效的基于CSP的群体感应调节剂，而在CSP序列中包含非天然氨基酸将赋予其对蛋白酶降解的抗性，这是候选药物的一个要求。
