State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Special Administrative Region; School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China.
Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region.
Bioorg Chem. 2024 Feb;143:106983. doi: 10.1016/j.bioorg.2023.106983. Epub 2023 Nov 23.
RNA polymerase is an essential enzyme involved in bacterial transcription, playing a crucial role in RNA synthesis. However, it requires the association with sigma factors to initiate this process. In our previous work, we utilized a structure-based drug discovery approach to create benzoyl and benzyl benzoic acid compounds. These compounds were designed based on the amino acid residues within the key binding site of sigma factors, which are crucial for their interaction with RNA polymerase. By inhibiting bacterial transcription, these compounds exhibited notable antimicrobial activity, and we coined them as sigmacidins to highlight their resemblance to sigma factors and the benzoic acid structure. In this study, we further modified the compound scaffolds and developed a series of sulfonamidyl benzoic acid derivatives. These derivatives displayed potent antimicrobial activity, with minimum inhibitory concentrations (MICs) as low as 1 µg/mL, demonstrating their efficacy against bacteria. Furthermore, these compounds demonstrated low cytotoxicity, indicating their potential as safe antimicrobial agents. To ascertain their mechanism of action in interfering with bacterial transcription, we conducted biochemical and cellular assays. Overall, this study showcases the effectiveness of sulfonamidyl benzoic acid derivatives as antimicrobial agents by targeting protein-protein interactions involving RNA polymerase and sigma factors. Their strong antimicrobial activity and low cytotoxicity implicate their potential in combating antibiotic-resistant bacteria.
RNA 聚合酶是一种参与细菌转录的必需酶，在 RNA 合成中起着至关重要的作用。然而，它需要与 sigma 因子结合才能启动这个过程。在我们之前的工作中，我们利用基于结构的药物发现方法来创建苯甲酰基和苯甲基苯甲酸化合物。这些化合物是根据 sigma 因子关键结合位点内的氨基酸残基设计的，这些残基对于它们与 RNA 聚合酶的相互作用至关重要。通过抑制细菌转录，这些化合物表现出显著的抗菌活性，我们将它们命名为 sigmacidins，以强调它们与 sigma 因子和苯甲酸结构的相似性。在本研究中，我们进一步修饰了化合物骨架，并开发了一系列磺酰胺基苯甲酸衍生物。这些衍生物表现出很强的抗菌活性，最低抑菌浓度（MIC）低至 1μg/mL，证明了它们对细菌的疗效。此外，这些化合物表现出低细胞毒性，表明它们有作为安全抗菌剂的潜力。为了确定它们在干扰细菌转录中的作用机制，我们进行了生化和细胞测定。总的来说，这项研究展示了磺酰胺基苯甲酸衍生物作为抗菌剂的有效性，通过靶向涉及 RNA 聚合酶和 sigma 因子的蛋白质-蛋白质相互作用。它们强大的抗菌活性和低细胞毒性表明它们在对抗抗生素耐药菌方面具有潜力。
