Development of triaryl antimicrobials by scaffold hopping from an aminopropanol hit targeting bacterial RNA polymerase-NusG interactions.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tiankuang Liu, Cheuk Hei Kan, Yingbo Zheng, Tsz Fung Tsang, Yanpeng Liu, Man Wai Tsang, Hantian Fang, Long Yin Lam, Xiao Yang, Cong Ma
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引用次数: 0

Abstract

Bacterial RNA polymerase (RNAP) requires the NusG factor to facilitate transcription, with the RNAP clamp-helix domain (CH) serving as the primary binding site for NusG and representing a promising target for antimicrobial intervention. In previous work, we unprecedentedly developed a pharmacophore model based on key clamp-helix residues (R270, R278, R281) at RNAP CH essential for NusG binding, which led to the identification of a hit compound exhibiting modest antimicrobial activity against Streptococcus pneumoniae. In this study, we designed a new class of triaryl inhibitors via scaffold hopping, substituting the linear structure of the hit compound with a benzene ring. Antimicrobial testing showed that several newly synthesised lead compounds achieved the minimum inhibitory concentration of 1 µg/mL against drug-resistant S. pneumoniae, superior to some marketed antibiotics. The following inhibitory and cell-based assays demonstrated the potential of these triaryl compounds as promising candidates for further development as novel antimicrobial agents.

利用氨基丙醇撞击靶向细菌RNA聚合酶nusg相互作用的支架跳变制备三芳基抗菌剂。
细菌RNA聚合酶(RNAP)需要NusG因子来促进转录,而RNAP夹-螺旋结构域(CH)是NusG的主要结合位点,是抗菌干预的一个有希望的靶点。在之前的工作中,我们史无前例地建立了一个基于NusG结合所必需的RNAP CH关键钳-螺旋残基(R270, R278, R281)的药效团模型,从而鉴定出一种对肺炎链球菌具有适度抗菌活性的hit化合物。在这项研究中,我们通过支架跳跃设计了一类新的三芳基抑制剂,用苯环取代了被击中化合物的线性结构。抗菌试验表明,几种新合成的先导化合物对耐药肺炎链球菌的最低抑菌浓度为1 μ g/mL,优于部分市售抗生素。以下的抑制和基于细胞的实验证明了这些三芳基化合物作为新型抗菌剂进一步开发的有希望的候选者的潜力。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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