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Rationally designed foldameric adjuvants enhance antibiotic efficacy via promoting membrane hyperpolarization
Molecular Systems Design & Engineering ( IF 3.2 ) Pub Date : 2021-11-11 , DOI: 10.1039/d1me00118c Kaushik Nath Bhaumik 1 , Anasztázia Hetényi 1 , Gábor Olajos 1 , Ana Martins 2 , Réka Spohn 2 , Lukács Németh 3 , Balázs Jojart 3 , Petra Szili 2, 4 , Anett Dunai 2 , Pramod K Jangir 2 , Lejla Daruka 2, 5 , Imre Földesi 6 , Diána Kata 5 , Csaba Pál 2 , Tamás A Martinek 1
Molecular Systems Design & Engineering ( IF 3.2 ) Pub Date : 2021-11-11 , DOI: 10.1039/d1me00118c Kaushik Nath Bhaumik 1 , Anasztázia Hetényi 1 , Gábor Olajos 1 , Ana Martins 2 , Réka Spohn 2 , Lukács Németh 3 , Balázs Jojart 3 , Petra Szili 2, 4 , Anett Dunai 2 , Pramod K Jangir 2 , Lejla Daruka 2, 5 , Imre Földesi 6 , Diána Kata 5 , Csaba Pál 2 , Tamás A Martinek 1
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The negative membrane potential of bacterial cells influences crucial cellular processes. Inspired by the molecular scaffold of the antimicrobial peptide PGLa, we have developed antimicrobial foldamers with a computer-guided design strategy. The novel PGLa analogues induce sustained membrane hyperpolarization. When co-administered as an adjuvant, the resulting compounds – PGLb1 and PGLb2 – have substantially reduced the level of antibiotic resistance of multi-drug resistant Escherichia coli, Klebsiella pneumoniae and Shigella flexneri clinical isolates. The observed antibiotic potentiation was mediated by hyperpolarization of the bacterial membrane caused by the alteration of cellular ion transport. Specifically, PGLb1 and PGLb2 are selective ionophores that enhance the Goldman–Hodgkin–Katz potential across the bacterial membrane. These findings indicate that manipulating bacterial membrane electrophysiology could be a valuable tool to overcome antimicrobial resistance.
中文翻译：
合理设计的折叠佐剂通过促进膜超极化增强抗生素功效
细菌细胞的负膜电位影响关键的细胞过程。受抗菌肽 PGLa 分子支架的启发，我们开发了采用计算机引导设计策略的抗菌折叠器。新型 PGLa 类似物可诱导持续的膜超极化。当作为佐剂共同给药时，产生的化合物 - PGLb1 和 PGLb2 - 显着降低了多重耐药大肠杆菌、肺炎克雷伯菌和福氏志贺氏菌临床分离株的抗生素耐药性水平。观察到的抗生素增强作用是由细胞离子运输改变引起的细菌膜超极化介导的。具体来说，PGLb1 和 PGLb2 是选择性离子载体，可增强跨细菌膜的 Goldman-Hodgkin-Katz 电位。这些发现表明，操纵细菌膜电生理学可能是克服抗菌素耐药性的宝贵工具。
更新日期：2021-11-24
中文翻译：
合理设计的折叠佐剂通过促进膜超极化增强抗生素功效
细菌细胞的负膜电位影响关键的细胞过程。受抗菌肽 PGLa 分子支架的启发，我们开发了采用计算机引导设计策略的抗菌折叠器。新型 PGLa 类似物可诱导持续的膜超极化。当作为佐剂共同给药时，产生的化合物 - PGLb1 和 PGLb2 - 显着降低了多重耐药大肠杆菌、肺炎克雷伯菌和福氏志贺氏菌临床分离株的抗生素耐药性水平。观察到的抗生素增强作用是由细胞离子运输改变引起的细菌膜超极化介导的。具体来说，PGLb1 和 PGLb2 是选择性离子载体，可增强跨细菌膜的 Goldman-Hodgkin-Katz 电位。这些发现表明，操纵细菌膜电生理学可能是克服抗菌素耐药性的宝贵工具。
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