State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment and SUSTech-HKU Joint Laboratories for Matrix Biology, Southern University of Science and Technology, Shenzhen, 518055, China.
Eur J Med Chem. 2020 Feb 15;188:112022. doi: 10.1016/j.ejmech.2019.112022. Epub 2019 Dec 30.
Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 μg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25-1 μg/mL vs. 1-64 μg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6-155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.
由于抗生素耐药性的出现，细菌性传染病已成为严重威胁公共健康的因素。为了克服抗生素耐药性，迫切需要新型抗生素。N-噻二唑-4-羟基-2-喹啉-3-甲酰胺是一种有潜力的新型抗菌药物，其一个衍生物被鉴定为抗金黄色葡萄球菌的抗菌药物。然而，尚未进行针对药效的结构优化。在本研究中，我们设计并合成了 37 个衍生物，并评估了它们对金黄色葡萄球菌 ATCC29213 的抗菌活性，从中鉴定出 10 种具有最低抑菌浓度（MIC）值低于 1μg/mL 的强效抗菌剂。随后，我们针对一组包括耐甲氧西林金黄色葡萄球菌在内的耐药临床分离株进行了细菌生长抑制试验，并在 HepG2 和 HUVEC 细胞上进行了细胞毒性试验。测试的化合物之一，命名为 1-乙基-4-羟基-2-氧代-N-(5-(噻唑-2-基)-1,3,4-噻二唑-2-基)-1,2-二氢喹啉-3-甲酰胺（g37），与万古霉素相比，在针对测试菌株的抗菌效力方面（MIC：0.25-1μg/mL 对 1-64μg/mL）和最佳选择性毒性（HepG2/MRSA，110.6 至 221.2；HUVEC/MRSA，77.6 至 155.2）方面均有 2 至 128 倍的提高。此外，综合评估表明，g37 在 20 代以上的传代过程中未诱导耐甲氧西林金黄色葡萄球菌产生耐药性，并且已被确认为一种杀菌、代谢稳定、具有口服活性的抗菌药物。更重要的是，我们已确定金黄色葡萄球菌 DNA 拓扑异构酶 B 为其潜在靶标，并通过分子对接提出了一种潜在的结合模式。综上所述，本研究报告了该化学系列中最有效的衍生物（g37）及其潜在靶标，为基于结构的药物设计技术进一步进行先导化合物优化奠定了坚实的基础。
