Drug Discovery and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, 66123, Saarbrücken, Germany.
Saarland University, Department of Pharmacy, Campus Building E8.1, 66123, Saarbrücken, Germany.
ChemMedChem. 2023 Oct 4;18(19):e202300346. doi: 10.1002/cmdc.202300346. Epub 2023 Sep 28.
Discovery of novel antibiotics needs multidisciplinary approaches to gain target enzyme and bacterial activities while aiming for selectivity over mammalian cells. Here, we report a multiparameter optimisation of a fragment-like hit that was identified through a structure-based virtual-screening campaign on Escherichia coli IspE crystal structure. Subsequent medicinal-chemistry design resulted in a novel class of E. coli IspE inhibitors, exhibiting activity also against the more pathogenic bacteria Pseudomonas aeruginosa and Acinetobacter baumannii. While cytotoxicity remains a challenge for the series, it provides new insights on the molecular properties for balancing enzymatic target and bacterial activities simultaneously as well as new starting points for the development of IspE inhibitors with a predicted new mode of action.
新型抗生素的发现需要多学科方法来获得靶酶和细菌活性，同时针对哺乳动物细胞具有选择性。在这里，我们报告了通过对大肠杆菌 IspE 晶体结构进行基于结构的虚拟筛选，对片段样命中的一个进行多参数优化。随后的药物化学设计产生了一类新型的大肠杆菌 IspE 抑制剂，对更具致病性的细菌铜绿假单胞菌和鲍曼不动杆菌也具有活性。虽然细胞毒性仍然是该系列的一个挑战，但它为平衡酶靶标和细菌活性的分子特性提供了新的见解，也为开发具有预测新作用模式的 IspE 抑制剂提供了新的起点。
