Design, Synthesis, and Biological Evaluation of 1,3,4-Thiadiazole Derivatives as Novel Potent Peptide Deformylase Inhibitors for Combating Drug-Resistant Gram-Positive and -Negative Bacteria

作者：Huayan Yang, Yaru Wang, Yujie Yang, Zhiqin Zhang, Fengfeng Li, Lingling Tao, Ling Han, Shenghai Guo, Ying Zhang, Yuqin Jiang, Junbiao Chang, Huayan Yang · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c02177 · 被引用次数：10 · 研究领域：Peptidase Inhibition and Analysis、Pneumocystis jirovecii pneumonia detection and treatment、Antibiotic Resistance in Bacteria

The prevalence of drug-resistant bacteria is a major challenge throughout the world, especially with respect to Gram-negative bacteria, such as drug-resistant Acinetobacter baumannii, 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 A. baumannii in a mouse model was achieved by a PDF inhibitor (compound 43 ). These findings can pave a way to new approaches to the development of novel broad-spectrum PDF inhibitors.