Ojah Emmanuel O, Gneid Hassan, Herschede Sarah R, Busschaert Nathalie
Chemistry, Tulane University, New Orleans, LA, United States.
Chemistry. 2024 Dec 10;30(69):e202402698. doi: 10.1002/chem.202402698. Epub 2024 Oct 29.
The World Health Organization has described the antimicrobial resistance crisis as one of the top ten global public health threats. New antimicrobial agents that can fight infections caused by antimicrobial resistant pathogens are therefore needed. A potential strategy is the development of small molecules that can selectively interact with bacterial membranes (or membranes of other microbial pathogens), and thereby rapidly kill the bacteria. Here, we report the structure-activity relationship within a group of 22 compounds that were designed to bind the bacterial lipid phosphatidylethanolamine (PE). Liposome-based studies reveal that the lipophilicity of the compounds has the strongest effect on both the affinity and selectivity for PE. The best results were obtained for compounds with logP≈3.75, which showed a 5x-7x selectivity for bacterial PE lipids over human PC (phosphatidylcholine) lipids. Furthermore, these compounds also showed potent antibacterial activity against the Gram-positive bacterium B. cereus, with minimum inhibitory concentrations (MICs) below 10 μM, a concentration where they showed minimal hemolytic activity against human red blood cells. These results not only show the possibility of PE-binding small molecules to function as antibiotics, but also provide guidelines for the development of compounds targeting other types of biologically relevant membrane lipids.
世界卫生组织已将抗菌药物耐药性危机列为全球十大公共卫生威胁之一。因此，需要能够对抗由抗菌药物耐药病原体引起的感染的新型抗菌药物。一种潜在的策略是开发能够与细菌膜（或其他微生物病原体的膜）选择性相互作用，从而快速杀死细菌的小分子。在此，我们报告了一组旨在结合细菌脂质磷脂酰乙醇胺（PE）的22种化合物的构效关系。基于脂质体的研究表明，这些化合物的亲脂性对PE的亲和力和选择性影响最大。logP≈3.75的化合物取得了最佳结果，其对细菌PE脂质的选择性比对人PC（磷脂酰胆碱）脂质高5至7倍。此外，这些化合物对革兰氏阳性菌蜡样芽孢杆菌也表现出强大的抗菌活性，最低抑菌浓度（MIC）低于10 μM，在该浓度下它们对人红细胞的溶血活性极小。这些结果不仅表明了结合PE的小分子作为抗生素发挥作用的可能性，还为开发针对其他类型生物相关膜脂质的化合物提供了指导。
