Chan Samuel J W, Zhang Kaixi, Zhu Ji-Yu, Bazan Guillermo C
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore, Singapore, 117543, Singapore.
Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, Singapore, 117585, Singapore.
Chemistry. 2023 May 8;29(26):e202203803. doi: 10.1002/chem.202203803. Epub 2023 Mar 6.
Conjugated oligoelectrolytes (COEs) are an emerging class of amphiphilic antimicrobial compounds with a modular molecular framework suitable for simple chemical derivatization. Here, a series of COE derivatives with a stilbene-conjugated segment and triphenylphosphonium (TPP) pendant groups was designed and synthesized to understand how lipophilic cationic groups impact antimicrobial activity. In vitro evaluations against ESKAPE pathogens showed broad-spectrum activity towards multi-drug resistant (MDR) bacteria and mycobacteria, with TPP groups enhancing antimicrobial activity towards clinically relevant Gram-negative strains compared to their ammonium analogues. We studied the interactions of DM6P, the most active TPP-COE compound, with various membrane assays. Treatment of bacterial cells with DM6P showed enhanced permeability of cell membranes without inducing the development of significant bacterial resistance. Moreover, DM6P eliminated 99.99 % of methicillin-resistant Staphyloccocus aureus (MRSA) in an in vivo wound model. These results represent a promising chemical strategy for increasing the activity spectrum of membrane-active COE antibiotics to tackle challenging drug-resistant targets.
共轭寡电解质（COEs）是一类新兴的两亲性抗菌化合物，具有适合简单化学衍生化的模块化分子框架。在此，设计并合成了一系列具有芪共轭片段和三苯基膦鎓（TPP）侧基的COE衍生物，以了解亲脂性阳离子基团如何影响抗菌活性。针对ESKAPE病原体的体外评估显示，其对多重耐药（MDR）细菌和分枝杆菌具有广谱活性，与铵类似物相比，TPP基团增强了对临床相关革兰氏阴性菌株的抗菌活性。我们研究了最具活性的TPP-COE化合物DM6P与各种膜分析方法的相互作用。用DM6P处理细菌细胞显示细胞膜通透性增强，且未诱导显著的细菌耐药性产生。此外，在体内伤口模型中，DM6P消除了99.99%的耐甲氧西林金黄色葡萄球菌（MRSA）。这些结果代表了一种有前景的化学策略，可扩大膜活性COE抗生素的活性谱，以应对具有挑战性的耐药靶点。
