The role of molecular arrangement of hydrophobic and hydrophilic groups for designing membrane-active molecules remains largely ambiguous. To explore this aspect, herein we report a series of membrane-active small molecules by varying the spatial distribution of hydrophobic groups. The two terminal amino groups of linear triamines such as diethylene triamine, bis(trimethylene)triamine, and bis(hexamethylene)triamine were conjugated with cationic amino acids bearing variable side chain hydrophobicity (such as diaminobutyric acid, ornithine, and lysine). The hydrophobicity was also modulated through conjugation of different long chain fatty acids with the central secondary amino group of the triamine. Molecules with constant backbone hydrophobicity displayed an enhanced antibacterial activity and decreased hemolytic activity upon increasing the side chain hydrophobicity of amino acids. On the other hand, increased hydrophobicity in the backbone introduced a slight hemolytic activity but a higher increment in antibacterial activity, resulting in better selective antibacterial compounds. The optimized lead compound derived from structure-activity-relationship (SAR) studies was the dodecanoyl analogue of a lysine series of compounds consisting of bis(hexamethylene)triamine as the backbone. This compound was active against various Gram-positive and Gram-negative bacteria at a low concentration (MIC ranged between 3.1 and 6.3 μg/mL) and displayed low toxicity toward mammalian cells (HC50 = 890 μg/mL and EC50 against HEK = 85 μg/mL). Additionally, it was able to kill metabolically inactive bacterial cells and eradicate preformed biofilms of MRSA. This compound showed excellent activity in a mouse model of skin infection with reduction of ∼4 log MRSA burden at 40 mg/kg dose without any sign of skin toxicity even at 200 mg/kg. More importantly, it revealed potent efficacy in an ex vivo model of human skin infection (with reduction of 85% MRSA burden at 50 μg/mL), which indicates great potential of the compound as an antibacterial agent to treat skin infections.

中文翻译：

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疏水调节的小抗菌分子根除对皮肤感染有效的生物膜。

疏水和亲水基团的分子排列在设计膜活性分子中的作用仍然是模棱两可的。为了探索这个方面，本文中我们通过改变疏水基团的空间分布来报道一系列膜活性小分子。线性三胺例如二亚乙基三胺，双（三亚甲基）三胺和双（六亚甲基）三胺的两个末端氨基与带有可变侧链疏水性的阳离子氨基酸（例如二氨基丁酸，鸟氨酸和赖氨酸）缀合。疏水性也通过不同的长链脂肪酸与三胺的中央仲氨基的缀合来调节。具有恒定骨架疏水性的分子在增加氨基酸的侧链疏水性时显示出增强的抗菌活性和降低的溶血活性。另一方面，主链中疏水性的增加引入了轻微的溶血活性，但抗菌活性却提高了，从而产生了更好的选择性抗菌化合物。来自结构-活性-关系（SAR）研究的优化的先导化合物是由双（六亚甲基）三胺为骨架的赖氨酸系列化合物的十二烷酰基类似物。该化合物在低浓度（MIC范围在3.1和6.3μg/ mL之间）对多种革兰氏阳性和革兰氏阴性细菌具有活性，并且对哺乳动物细胞（HC50 = 890μg/ mL，EC50对HEK = 85μg）的毒性低。 / mL）。另外，它能够杀死代谢不活跃的细菌细胞，并根除预先形成的MRSA生物膜。该化合物在小鼠皮肤感染模型中显示出优异的活性，在40 mg / kg剂量下可降低〜4 log MRSA负担，即使在200 mg / kg时也没有任何皮肤毒性的迹象。更重要的是，它显示了在人类皮肤感染的离体模型中的有效功效（在50μg/ mL浓度下MRSA负担降低了85％），这表明该化合物作为抗菌剂具有治疗皮肤感染的巨大潜力。