Jennings James, Ašćerić Dunja, Malanovic Nermina, Pabst Georg
Institute of Molecular Biosciences, University of Graz, NAWI Graz, 8010 Graz, Austria.
Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria.
Antibiotics (Basel). 2023 Aug 9;12(8):1300. doi: 10.3390/antibiotics12081300.
Membrane-active molecules provide a promising strategy to target and kill pathogenic bacteria. Understanding how specific molecular features drive interactions with membrane components and subsequently cause disruption that leads to antimicrobial activity is a crucial step in designing next-generation treatments. Here, we test a library of lipid-like compounds (lipidoids) against Gram-negative bacteria to garner in-depth structure-activity relationships using antimicrobial assays. Modular lipidoid molecules were synthesized in high-throughput, such that we could analyze 104 compounds with variable combinations of hydrophobic tails and cationic headgroups. Antibacterial activity was strongly correlated to specific structural features, including tail hydrophobicity and headgroup charge density, and also to the overall molecular shape and propensity for self-assembly into curved liquid crystalline phases. Dye permeabilization assays showed that membranes were permeabilized by lipidoids, confirming their membrane-active nature. The reduced permeabilization, as compared to Gram-positive , alludes to the challenge of permeabilizing the additional outer membrane layer of . The effect of headgroup solubility in gemini-type lipidoids was also demonstrated, revealing that a headgroup with a more hydrophilic spacer between amine groups had enhanced activity against but not . This provides insight into features enabling outer membrane penetration and governing selectivity between bacterial species.
膜活性分子为靶向和杀死病原菌提供了一种很有前景的策略。了解特定分子特征如何驱动与膜成分的相互作用，进而导致破坏并产生抗菌活性，是设计下一代治疗方法的关键一步。在此，我们使用抗菌试验对一系列类脂化合物（脂质体）针对革兰氏阴性菌进行测试，以获得深入的构效关系。模块化脂质体分子通过高通量合成，这样我们就可以分析104种具有不同疏水尾部和阳离子头部基团组合的化合物。抗菌活性与特定结构特征密切相关，包括尾部疏水性和头部基团电荷密度，还与整体分子形状以及自组装成弯曲液晶相的倾向有关。染料通透性试验表明，脂质体可使细胞膜通透性增加，证实了它们的膜活性性质。与革兰氏阳性菌相比，通透性降低暗示了穿透革兰氏阴性菌额外外膜层的挑战。还证明了头部基团在双子型脂质体中的溶解性影响，表明胺基之间具有更亲水间隔基的头部基团对革兰氏阴性菌具有增强的活性，但对革兰氏阳性菌则不然。这为了解实现外膜穿透以及控制细菌物种间选择性的特征提供了见解。
