High antimicrobial effectiveness with low hemolytic and cytotoxic activity for PEG/quaternary copolyoxetanes.
High antimicrobial effectiveness with low hemolytic and cytotoxic activity for PEG/quaternary copolyoxetanes.
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DOI：
10.1021/bm401794p
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发表时间：
2014-02-10
影响因子：
6.2
通讯作者：
Wynne, Kenneth J.
中科院分区：
文献类型：
--
作者：
King, Allison;Chakrabarty, Souvik;Zhang, Wei;Zeng, Xiaomei;Ohman, Dennis E.;Wood, Lynn F.;Abraham, Sheena;Rao, Raj;Wynne, Kenneth J.
研究了季铵盐/聚乙二醇共聚氧烷的烷基链长对溶液抑菌效果、溶血活性和细胞毒性的影响。以单体3-((4-溴丁氧基)甲基)-3-甲基氧烷(BBOX)和3-((2-(2-methoxyethoxy)ethoxy)methyl)-3-methyloxetane(ME2Ox)为原料，通过阳离子开环聚合制备了前驱体P[(BBOX)(ME2Ox)-50：50-4 kDa]共聚氧杂环己烷。通过1H核磁共振波谱确证了共聚物组成为1：1，分子量为4 kDa。用一系列叔胺取代C-BR后，得到了离子液体CX-50共聚氧杂环己烷，其中50是四元重复单元的摩尔百分比，“x”是季烷基链长度(2、6、8、10、12、14或16个碳)。调制差示扫描量热仪研究表明，−40和−60°C之间的玻璃化转变温度和C14-50和C16-50的熔融吸热曲线。测定了大肠埃希菌、金黄色葡萄球菌和铜绿假单胞菌的最低抑菌浓度(MIC)。发现MIC与烷基链长有系统的依赖关系。最有效的抗菌剂是C6-50到C12-50。C8-50对大肠杆菌、金黄色葡萄球菌和铜绿假单胞菌的MIC值分别为4μg/m L、2μg/m L和24μg/m L。在5×MIC条件下，C8-50对108CFU/mL的金黄色葡萄球菌、大肠杆菌和铜绿假单胞菌的1 h杀灭率为99%，1h的对数减少率分别为7、3和5。为了进一步了解聚阳离子与细菌膜的相互作用，描述了一个基于大肠杆菌尺寸的几何模型，该模型提供了能够化学吸附的聚阳离子的最大数量的估计。估算了相对分子质量为5 kDa的聚阳离子C8-50的链尺寸。考虑到聚阳离子化学吸附的近似值，令人惊讶的是，基于几何考虑的计算得出C8-50浓度在最低抑菌浓度的2倍内，对大肠杆菌为4.0(±1.2)μg/mL。CX-50共聚氧杂环己烷对人红细胞、人皮肤成纤维细胞和人包皮成纤维细胞的细胞毒性较低。相对于细胞裂解，细菌杀灭的选择性是迄今为止报道的聚阳离子中最高的，这表明了良好的生物相容性前景。
The alkyl chain length of quaternary ammonium/PEG copolyoxetanes has been varied to discern effects on solution antimicrobial efficacy, hemolytic activity and cytotoxicity. Monomers 3-((4-bromobutoxy)methyl)-3-methyloxetane (BBOx) and 3-((2-(2-methoxyethoxy)ethoxy)methyl)-3-methyloxetane (ME2Ox) were used to prepare precursor P[(BBOx)(ME2Ox)-50:50–4 kDa] copolyoxetane via cationic ring opening polymerization. The 1:1 copolymer composition and Mn (4 kDa) were confirmed by 1H NMR spectroscopy. After C–Br substitution by a series of tertiary amines, ionic liquid Cx-50 copolyoxetanes were obtained, where 50 is the mole percent of quaternary repeat units and “x” is quaternary alkyl chain length (2, 6, 8, 10, 12, 14, or 16 carbons). Modulated differential scanning calorimetry (MDSC) studies showed Tgs between −40 and −60 °C and melting endotherms for C14–50 and C16–50. Minimum inhibitory concentrations (MIC) were determined for Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. A systematic dependence of MIC on alkyl chain length was found. The most effective antimicrobials were in the C6–50 to C12–50 range. C8–50 had better overall performance with MICs of 4 μg/mL, E. coli; 2 μg/mL, S. aureus; and 24 μg/mL, P. aeruginosa. At 5 × MIC, C8–50 effected >99% kill in 1 h against S. aureus, E. coli, and P. aeruginosa challenges of 108 cfu/mL; log reductions (1 h) were 7, 3, and 5, respectively. To provide additional insight into polycation interactions with bacterial membranes, a geometric model based on the dimensions of E. coli is described that provides an estimate of the maximum number of polycations that can chemisorb. Chain dimensions were estimated for polycation C8–50 with a molecular weight of 5 kDa. Considering the approximations for polycation chemisorption (PCC), it is surprising that a calculation based on geometric considerations gives a C8–50 concentration within a factor of 2 of the MIC, 4.0 (±1.2) μg/mL for E. coli. Cx-50 copolyoxetane cytotoxicity was low for human red blood cells, human dermal fibroblasts (HDF), and human foreskin fibroblasts (HFF). Selectivities for bacterial kill over cell lysis were among the highest ever reported for polycations indicating good prospects for biocompatibility.
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影响因子：
6.2
作者：
Gabriel GJ;Madkour AE;Dabkowski JM;Nelson CF;Nüsslein K;Tew GN
通讯作者：
Tew GN
影响因子：
15
作者：
Ilker, MF;Nüsslein, K;Coughlin, EB
通讯作者：
Coughlin, EB
影响因子：
6.2
作者：
Albert, M;Feiertag, P;Hönig, H
通讯作者：
Hönig, H
影响因子：
2.5
作者：
Eren, Tarik;Som, Abhigyan;Tew, Gregory N.
通讯作者：
Tew, Gregory N.
影响因子：
4.9
作者：
Chin, Judy N.;Rybak, Michael J.;Savage, Paul B.
通讯作者：
Savage, Paul B.