Anionic Self-Assembling Supramolecular Enhancers of Antimicrobial Efficacy against Gram-Negative Bacteria
Anionic Self-Assembling Supramolecular Enhancers of Antimicrobial Efficacy against Gram-Negative Bacteria
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DOI：
10.1002/adtp.202200024
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发表时间：
2022-03-31
影响因子：
4.6
通讯作者：
Hiscock, Jennifer R.
中科院分区：
文献类型：
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作者：
Boles, Jessica E.;Williams, George T.;Hiscock, Jennifer R.
由于迫在眉睫的抗菌素耐药性危机，迫切需要新的抗菌素治疗方法。对于难以治疗的革兰氏阴性菌尤其如此，因为许多抗菌剂无法穿过细胞膜进入细胞内部，从而引发治疗反应。本文提供了使用阴离子超分子自结合两亲体（SSAs）作为抗革兰氏阴性菌常用抗菌药物的抗菌功效增强剂的证据，这些抗菌药物已知对革兰氏阴性菌具有耐药性。SSAs与抗菌剂联合使用可使传统上难以治疗的铜绿假单胞菌对利福平和新生物霉素都敏感，由此可以阐明结构活性关系。定量荧光显微镜显示，膜渗透可能是SSAs增强药物功效的作用方式。这些结果为抗菌佐剂设计提供了一种替代策略，将焦点扩展到阳离子肽和阴离子小分子领域。最后，通过定量核磁共振、张力测定、动态光散射和zeta电位研究，研究了这些抗菌剂存在下SSA的自组装，证明了这些药物对SSA自结合事件的影响。
As a result of the looming antimicrobial resistance crisis, there is an urgent need for novel antimicrobial treatments. This is particularly true for hard-to-treat Gram-negative bacteria, as many antimicrobial agents are unable to cross the cell membrane to gain access to the cell interior, and thus elicit a therapeutic response. Herein, evidence is provided of the use of anionic supramolecular self-associating amphiphiles (SSAs) as antimicrobial efficacy enhancers for commonly used antimicrobial agents, to which there is known resistance, against Gram-negative bacteria. The co-administration of the SSAs with antimicrobials is shown to sensitize traditionally hard to treat Pseudomonas aeruginosa to both rifampicin and novobiocin, from which structure activity relationships can be elucidated. Quantitative fluorescence microscopy is performed, indicating membrane permeabilization to be the likely mode of action of drug efficacy enhancement by the SSAs. These results offer an alternative strategy in antimicrobial adjuvant design, expanding focus beyond cationic peptides and into the realm of anionic small molecules. Finally, the self-assembly of the SSAs in the presence of these antimicrobials is investigated through a combination of quantitative NMR, tensiometry, dynamic light scattering, and zeta potential studies, demonstrating the impact of these agents on SSA self-association events.