Hydrophobicity-Modulated Small Antibacterial Molecule Eradicates Biofilm with Potent Efficacy against Skin Infections.
Hydrophobicity-Modulated Small Antibacterial Molecule Eradicates Biofilm with Potent Efficacy against Skin Infections.
复制标题
疏水性调节的抗菌小分子可消除生物膜，对皮肤感染具有强大的功效。
DOI：
10.1021/acsinfecdis.9b00334
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发表时间：
2020
影响因子：
5.3
通讯作者：
Konai MM
中科院分区：
文献类型：
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作者：
Konai MM
疏水基团和亲水基团的分子排列在设计膜活性分子中的作用仍然很模糊。为了探索这个方面，我们在本文中通过改变疏水基团的空间分布报告了一系列膜活性小分子。直链三胺如二亚乙基三胺、双(三亚甲基)三胺和双(六亚甲基)三胺的两个末端氨基与具有可变侧链疏水性的阳离子氨基酸(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心仲氨基的缀合来调节。具有恒定主链疏水性的分子在增加氨基酸侧链疏水性后表现出增强的抗菌活性和降低的溶血活性。另一方面，主链疏水性的增加带来了轻微的溶血活性，但抗菌活性更高，从而产生更好的选择性抗菌化合物。从结构-活性-关系（SAR）研究中得出的优化先导化合物是由双（六亚甲基）三胺作为主链组成的赖氨酸系列化合物的十二酰基类似物。该化合物在低浓度下对多种革兰氏阳性和革兰氏阴性细菌具有活性（MIC 范围在 3.1 至 6.3 μg/mL 之间），并且对哺乳动物细胞显示出低毒性（HC50= 890 μg/mL，针对 HEK 的 EC50 = 85 μg/mL）。此外，它还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。该化合物在皮肤感染小鼠模型中表现出优异的活性，在 40 mg/kg 剂量下可减少约 4 log MRSA 负荷，即使在 200 mg/kg 剂量下也没有任何皮肤毒性迹象。更重要的是，它在人类皮肤感染的离体模型中显示出强大的功效（在 50 μg/mL 时减少 85% MRSA 负荷），这表明该化合物作为治疗皮肤感染的抗菌剂具有巨大潜力。
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 EC50against 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.