Milly Tahmina A, Engler Emilee R, Chichura Kylie S, Buttner Alec R, Koirala Bimal, Tal-Gan Yftah, Bertucci Michael A
Department of Chemistry, University of Nevada, Reno, 1664 North Virginia Street, Reno, NV 89557, USA.
Department of Chemistry, Moravian College, 1200 Main Street, Bethlehem, PA 18018, USA.
Chembiochem. 2021 Jun 2;22(11):1940-1947. doi: 10.1002/cbic.202000876. Epub 2021 Apr 7.
Streptococcus pneumoniae (pneumococcus) is a human pathobiont that causes drastic antibiotic-resistant infections and is responsible for millions of deaths universally. Pneumococcus pathogenicity relies on the competence-stimulating peptide (CSP)-mediated quorum-sensing (QS) pathway that controls competence development for genetic transformation and, consequently, the spread of antibiotic resistance and virulence genes. Modulation of QS in S. pneumoniae can therefore be used to enervate pneumococcal infectivity as well as minimize the susceptibility to resistance development. In this work, we sought to optimize the interaction of CSP1 with its cognate transmembrane histidine kinase receptor (ComD1) through substitution of proteogenic and nonproteogenic amino acids on the hydrophobic binding face of CSP1. The findings from this study not only provided additional structure-activity data that are significant in optimizing CSP1 potency, but also led to the development of potent QS modulators. These CSP-based QS modulators could be used as privileged scaffolds for the development of antimicrobial agents against pneumococcal infections.
肺炎链球菌是一种人类致病共生菌，可引发严重的抗生素耐药性感染，全球范围内导致数百万人死亡。肺炎链球菌的致病性依赖于由感受态刺激肽（CSP）介导的群体感应（QS）途径，该途径控制着遗传转化的感受态发育，进而导致抗生素抗性和毒力基因的传播。因此，调节肺炎链球菌中的群体感应可用于削弱肺炎链球菌的感染性，并最大限度地降低其产生耐药性的易感性。在这项研究中，我们试图通过替换CSP1疏水结合面上的蛋白质氨基酸和非蛋白质氨基酸，来优化CSP1与其同源跨膜组氨酸激酶受体（ComD1）之间的相互作用。这项研究的结果不仅提供了对优化CSP1效力具有重要意义的额外构效关系数据，还促成了强效群体感应调节剂的开发。这些基于CSP的群体感应调节剂可作为开发抗肺炎链球菌感染抗菌剂的优势骨架。
