Mechanism of Antibacterial Activity of Choline-Based Ionic Liquids (CAGE)
Mechanism of Antibacterial Activity of Choline-Based Ionic Liquids (CAGE)
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DOI：
10.1021/acsbiomaterials.8b00486
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发表时间：
2018-07-01
影响因子：
5.8
通讯作者：
Mitragotri, Samir
中科院分区：
文献类型：
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作者：
Ibsen, Kelly N.;Ma, Huilin;Mitragotri, Samir
抗生素抗药性微生物的不断出现严重耗尽了我们的有效抗菌药物库。离子液体 (IL) 作为抗菌剂显示出巨大的前景，但了解对细菌细胞的攻击机制是确保基于 IL 的杀菌剂设计以最小的毒性提供最大功效的关键，同时还避免目标生物体产生耐药性的可能性。在这里，我们报告了一组基于胆碱和香叶酸 (CAGE) 的 IL 的抗菌特性，并确定了它们与大肠杆菌革兰氏阴性细胞壁相互作用的机制。 CAGE 被设想为一种治疗皮肤局部感染的抗菌剂。我们早期的工作表明，CAGE 对多种细菌、真菌和病毒物种都非常有效，并且对人体细胞无害。这种组合使 CAGE 成为人类使用的理想抗菌剂。合成了四种具有不同胆碱和香叶酸比例的 CAGE 变体并测试了它们的抗菌活性（1:4、1:2、1:1 和 2:1 胆碱:香叶酸）。杀死大肠杆菌所需的最低杀菌浓度与香叶酸含量相关。通过分子动力学 (MD) 模拟，我们确定了 CAGE 对大肠杆菌膜的作用机制，即胆碱被带负电的细胞膜吸引，从而将香叶酸插入脂质双层中。通过流式细胞术和扫描电子显微镜用碘化丙啶染色证实细胞膜的破坏。对处理细胞的傅里叶变换红外光谱分析显示，脂质谱发生了类似于相变的改变，表明脂质双层构象被破坏。反复暴露于 CAGE 的大肠杆菌细胞并未表现出耐药性。这项研究提供了基于胆碱的 IL 对革兰氏阴性菌作用的基本机制，并证明了 CAGE 作为治疗感染的强大抗菌剂的前景。
The continued emergence of antibiotic-resistant organisms has severely depleted our arsenal of effective antimicrobials. Ionic liquids (ILs) show great promise as antibacterial agents but understanding the mechanism of attack on bacterial cells is key to ensuring that design of IL-based biocides impart maximum efficacy with minimal toxicity, while also avoiding the potential for the target organisms to become resistant. Here we report the antibacterial attributes of a set of choline and geranate (CAGE)-based ILs and identify the mechanism by which they interact with the Gram-negative cell wall of Escherichia coli. CAGE is envisaged as an antimicrobial agent to treat topical infections in skin. Our earlier work has shown that CAGE is highly effective across a breadth of bacterial, fungal, and viral species and is benign to human cells. This combination makes CAGE an ideal antimicrobial for human use. Four CAGE variants with varying ratios of choline and geranic acid were synthesized and tested for their antibacterial activity (1:4, 1:2, 1:1, and 2:1 choline:geranic acid). The minimum bactericidal concentration required to kill E. coli correlated with the geranic acid content. Using molecular dynamics (MD) simulations, we identified the mechanism of CAGE action on the E. coli membrane, namely that choline is attracted to the negatively charged cell membrane and consequently inserts geranic acid into the lipid bilayer. The disruption of the cell membrane was confirmed with propidium iodide staining via flow cytometry and scanning electron microscopy. Fourier Transform infrared spectroscopic analysis of treated cells showed an altered lipid profile similar to phase transition, indicating the disruption of the lipid bilayer conformation. E. coli cells repeatedly exposed to CAGE did not exhibit resistance. This study provides the fundamental mechanism of the action of choline-based ILs on Gram-negative bacteria and demonstrates the promise of CAGE as a powerful antimicrobial agent to treat infections.