Yang Shouning, Wang Yaru, Yang Yujie, Zhang Zhiqin, Li Fengfeng, Tao Lingling, Han Ling, Guo Shenghai, Zhang Ying, Jiang Yuqin, Chang Junbiao, Yang Huayan
State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, NMPA Key Laboratory for Research and Evaluation of Innovative Drug, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China.
Shanghai Applied Radiation Institute, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, P. R. China.
J Med Chem. 2025 Feb 13;68(3):2942-2962. doi: 10.1021/acs.jmedchem.4c02177. Epub 2025 Jan 7.
The prevalence of drug-resistant bacteria is a major challenge throughout the world, especially with respect to Gram-negative bacteria, such as drug-resistant , which are regarded as the greatest bacterial threat to human health by the World Health Organization (WHO). In this work, 1,3,4-thiadiazole was introduced into the main skeleton of the classical peptidomimetic peptide deformylase (PDF) inhibitor in pursuit of highly efficient and broad-spectrum bacteriostatic drugs. Upon detailed structure-activity relationship study, PDF inhibitors that possess satisfactory activity against both Gram-positive and Gram-negative bacteria as well as a lower potential for methemoglobin toxicity were screened out. The mechanism of the empowered antibacterial activity against Gram-negative bacteria was also investigated. Finally, for the first time, remarkable protective efficacy against drug-resistant in a mouse model was achieved by a PDF inhibitor (compound ). These findings can pave a way to new approaches to the development of novel broad-spectrum PDF inhibitors.
耐药菌的流行是全球面临的一项重大挑战，尤其是对于革兰氏阴性菌，如耐药菌，世界卫生组织（WHO）将其视为对人类健康最大的细菌威胁。在这项工作中，将1,3,4-噻二唑引入经典拟肽类肽脱甲酰基酶（PDF）抑制剂的主要骨架中，以寻求高效、广谱的抑菌药物。通过详细的构效关系研究，筛选出了对革兰氏阳性菌和革兰氏阴性菌均具有满意活性且高铁血红蛋白毒性较低的PDF抑制剂。还研究了增强的抗革兰氏阴性菌抗菌活性的机制。最后，首次通过一种PDF抑制剂（化合物）在小鼠模型中对耐药菌取得了显著的保护效果。这些发现可为新型广谱PDF抑制剂开发的新方法铺平道路。
