Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
Eur J Med Chem. 2023 Aug 5;256:115452. doi: 10.1016/j.ejmech.2023.115452. Epub 2023 May 3.
The emergence of pathogenic and drug-resistant microorganisms seriously threatens public safety. This work constructed a unique type of thiazolyl hydrazineylidenyl indolones (THIs) to combat global microbial multidrug-resistance. Bioactive evaluation discovered that some target THIs displayed much superior antimicrobial efficacy than clinical chloromycetin, norfloxacin, cefdinir or fluconazole against the tested strains. Eminently, butyl THI 6c displayed a broad antimicrobial spectrum with low MICs of 0.25-1 μg/mL. The highly active THI 6c not only showed low cytotoxicity and hemolysis, rapidly bactericidal ability, good antibiofilm activity and promising pharmacokinetic properties, but also could significantly impede the development of bacterial resistance. Preliminary exploration of antibacterial mechanism revealed that THI 6c could effectively penetrate the cell membrane of MRSA and embed DNA to form 6c‒DNA supramolecular complex and thus hinder DNA replication. Moreover, THI 6c could reduce cell metabolic activity, which might be attributed to the fact that THI 6c could target the pyruvate kinase of MRSA and interfere with the function of the enzyme. These results provided powerful information for further developing thiazolyl hydrazineylidenyl indolones as new broad-spectrum antimicrobial agents.
致病微生物和耐药微生物的出现严重威胁着公共安全。本研究构建了一种独特的噻唑基腙亚基吲哚酮（THI），以对抗全球微生物的多药耐药性。生物活性评估发现，一些目标 THI 对测试菌株的抗菌效果明显优于临床使用的氯霉素、诺氟沙星、头孢地尼或氟康唑。突出的是，丁基 THI 6c 对多种微生物表现出广谱的抗菌活性，MIC 值低至 0.25-1μg/mL。高活性的 THI 6c 不仅表现出低细胞毒性和溶血活性、快速杀菌能力、良好的抗生物膜活性和有前景的药代动力学特性，而且还可以显著阻碍细菌耐药性的发展。抗菌机制的初步探索表明，THI 6c 可以有效地穿透 MRSA 的细胞膜，并嵌入 DNA 形成 6c-DNA 超分子复合物，从而阻碍 DNA 复制。此外，THI 6c 可以降低细胞代谢活性，这可能归因于 THI 6c 可以靶向 MRSA 的丙酮酸激酶并干扰酶的功能。这些结果为进一步开发噻唑基腙亚基吲哚酮作为新型广谱抗菌药物提供了有力信息。
