Milly Tahmina A, Buttner Alec R, Rieth Naomi, Hutnick Elizabeth, Engler Emilee R, Campanella Alexandra R, Lella Muralikrishna, Bertucci Michael A, Tal-Gan Yftah
Department of Chemistry, University of Nevada, Reno 1664 North Virginia Street Reno Nevada 89557 USA
Department of Chemistry, Moravian University 1200 Main St. Bethlehem PA 18018 USA.
RSC Chem Biol. 2022 Jan 28;3(3):301-311. doi: 10.1039/d1cb00224d. eCollection 2022 Mar 9.
The prompt appearance of multiantibiotic-resistant bacteria necessitates finding alternative treatments that can attenuate bacterial infections while minimizing the rate of antibiotic resistance development. , a notorious human pathogen, is responsible for severe antibiotic-resistant infections. Its pathogenicity is influenced by a cell-density communication system, termed quorum sensing (QS). As a result, controlling QS through the development of peptide-based QS modulators may serve to attenuate pneumococcal infections. Herein, we set out to evaluate the impact of the introduction of bulkier, nonproteogenic side-chain residues on the hydrophobic binding face of CSP1 to optimize receptor-binding interactions in both of the specificity groups. Our results indicate that these substitutions optimize the peptide-protein binding interactions, yielding several pneumococcal QS modulators with high potency. Moreover, pharmacological evaluation of lead analogs revealed that the incorporation of nonproteogenic amino acids increased the peptides' half-life towards enzymatic degradation while remaining nontoxic. Overall, our data convey key considerations for SAR using nonproteogenic amino acids, which provide analogs with better pharmacological properties.
多重耐药细菌的迅速出现使得有必要寻找替代治疗方法，既能减轻细菌感染，又能将抗生素耐药性的发展速度降至最低。肺炎链球菌是一种臭名昭著的人类病原体，会导致严重的耐药感染。其致病性受一种称为群体感应（QS）的细胞密度通信系统影响。因此，通过开发基于肽的QS调节剂来控制QS可能有助于减轻肺炎球菌感染。在此，我们着手评估在CSP1的疏水结合面上引入更大的非蛋白ogenic侧链残基对优化两个特异性组中受体结合相互作用的影响。我们的结果表明，这些取代优化了肽-蛋白质结合相互作用，产生了几种高效的肺炎球菌QS调节剂。此外，先导类似物的药理学评估表明，非蛋白ogenic氨基酸的掺入增加了肽对酶促降解的半衰期，同时保持无毒。总体而言，我们的数据传达了使用非蛋白ogenic氨基酸进行构效关系研究的关键考虑因素，这些氨基酸为类似物提供了更好的药理学特性。
