European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-08-18 , DOI: 10.1016/j.ejmech.2020.112671 Jiqing Ye 1 , Adrian Jun Chu 2 , Lin Lin 2 , Shu Ting Chan 1 , Rachel Harper 2 , Min Xiao 3 , Irina Artsimovitch 4 , Zhong Zuo 3 , Cong Ma 1 , Xiao Yang 2
Transcription is an essential biological process in bacteria requiring a core enzyme, RNA polymerase (RNAP). Bacterial RNAP is catalytically active but requires sigma (σ) factors for transcription of natural DNA templates. σ factor binds to RNAP to form a holoenzyme which specifically recognizes a promoter, melts the DNA duplex, and commences RNA synthesis. Inhibiting the binding of σ to RNAP is expected to inhibit bacterial transcription and growth. We previously identified a triaryl hit compound that mimics σ at its major binding site of RNAP, thereby inhibiting the RNAP holoenzyme formation. In this study, we modified this scaffold to provide a series of benzyl and benzoyl benzoic acid derivatives possessing improved antimicrobial activity. A representative compound demonstrated excellent activity against Staphylococcus epidermidis with minimum inhibitory concentrations reduced to 0.5 μg/mL, matching that of vancomycin. The molecular mechanism of inhibition was confirmed using biochemical and cellular assays. Low cytotoxicity and metabolic stability of compounds demonstrated the potential for further studies.
中文翻译:
细菌 RNA 聚合酶-西格玛因子相互作用的苄基和苯甲酰苯甲酸抑制剂。
转录是细菌中必不可少的生物过程,需要核心酶 RNA 聚合酶 (RNAP)。细菌 RNAP 具有催化活性,但需要 sigma (σ) 因子来转录天然 DNA 模板。σ 因子与 RNAP 结合形成全酶,该全酶特异性识别启动子、解链 DNA 双链体并开始 RNA 合成。抑制 σ 与 RNAP 的结合有望抑制细菌转录和生长。我们之前确定了一种三芳基命中化合物,它在其主要的 RNAP 结合位点模拟 σ,从而抑制了 RNAP 全酶的形成。在这项研究中,我们修改了该支架以提供一系列具有改进抗菌活性的苄基和苯甲酰基苯甲酸衍生物。一种代表性化合物表现出优异的抗表皮葡萄球菌的最低抑菌浓度降至 0.5 μg/mL,与万古霉素相匹配。使用生化和细胞分析证实了抑制的分子机制。化合物的低细胞毒性和代谢稳定性证明了进一步研究的潜力。