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Effect of Composition on Antibacterial Activity of Sequence-Defined Cationic Oligothioetheramides
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-05-11 00:00:00 , DOI: 10.1021/acsinfecdis.8b00079 Christine M. Artim 1 , Ngoc N. Phan 1 , Christopher A. Alabi 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-05-11 00:00:00 , DOI: 10.1021/acsinfecdis.8b00079 Christine M. Artim 1 , Ngoc N. Phan 1 , Christopher A. Alabi 1
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In response to the urgent need for new antibiotic development strategies, antimicrobial peptides and their synthetic mimetics are being investigated as promising alternatives to traditional antibiotics. To facilitate their development into clinically viable candidates, we need to understand what molecular features and physicochemical properties are needed to induce cell death. Within the context of sequence-defined oligothioetheramides (oligoTEAs), we explore the impact of the cationic pendant group and backbone hydrophobicity on the potency and selectivity of antibacterial oligoTEAs. Through antibacterial, cytotoxicity, membrane destabilization, and membrane depolarization assays, we find a strong dependency on the nature of the cationic group and improved selectivity toward bacteria by tuning backbone hydrophobicity. In particular, compounds with the guanidinium headgroup are more potent than those with amines. Finally, we identify a promising oligoTEA, PDT-4G, with enhanced activity in vitro (minimum inhibitory concentration (MIC) ∼ 0.78 μM) and moderate activity in a mouse thigh infection model of methicillin-resistant Staphylococcus aureus. The studies outlined in this work provide insights into the effect of macromolecular physicochemical properties on antibacterial potency. This knowledge base will be vital for researchers engaged in the ongoing development of clinically viable antibacterial agents.
中文翻译：
成分对序列定义的阳离子寡硫醚酰胺类抗菌活性的影响
为响应对新抗生素开发策略的迫切需求，正在研究抗菌肽及其合成模拟物，以作为传统抗生素的有前途的替代品。为了促进它们发展为临床上可行的候选物，我们需要了解诱导细胞死亡所需的分子特征和理化特性。在序列定义的寡硫醚酰胺（oligoTEA）的上下文中，我们探索了阳离子侧基和主链疏水性对抗菌oligoTEA效力和选择性的影响。通过抗菌，细胞毒性，膜去稳定和膜去极化测定，我们发现对阳离子基团的性质有很强的依赖性，并通过调节主链疏水性改善了对细菌的选择性。尤其是，具有胍基头基的化合物比具有胺的化合物更有效。最后，我们确定了具有增强活性的有前途的oligoTEA PDT-4G在耐甲氧西林金黄色葡萄球菌的小鼠大腿感染模型中，体外（最低抑菌浓度（MIC）约为0.78μM）和中等活性。这项工作中概述的研究提供了对高分子理化性质对抗菌效力的影响的见解。该知识库对于从事临床上可行的抗菌剂开发的研究人员至关重要。
更新日期：2018-05-11
中文翻译：
成分对序列定义的阳离子寡硫醚酰胺类抗菌活性的影响
为响应对新抗生素开发策略的迫切需求，正在研究抗菌肽及其合成模拟物，以作为传统抗生素的有前途的替代品。为了促进它们发展为临床上可行的候选物，我们需要了解诱导细胞死亡所需的分子特征和理化特性。在序列定义的寡硫醚酰胺（oligoTEA）的上下文中，我们探索了阳离子侧基和主链疏水性对抗菌oligoTEA效力和选择性的影响。通过抗菌，细胞毒性，膜去稳定和膜去极化测定，我们发现对阳离子基团的性质有很强的依赖性，并通过调节主链疏水性改善了对细菌的选择性。尤其是，具有胍基头基的化合物比具有胺的化合物更有效。最后，我们确定了具有增强活性的有前途的oligoTEA PDT-4G在耐甲氧西林金黄色葡萄球菌的小鼠大腿感染模型中，体外（最低抑菌浓度（MIC）约为0.78μM）和中等活性。这项工作中概述的研究提供了对高分子理化性质对抗菌效力的影响的见解。该知识库对于从事临床上可行的抗菌剂开发的研究人员至关重要。
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