Nanocarriers with conjugated antimicrobials to eradicate pathogenic biofilms evaluated in murine in vivo and human ex vivo infection models
Nanocarriers with conjugated antimicrobials to eradicate pathogenic biofilms evaluated in murine in vivo and human ex vivo infection models
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在小鼠体内和人类离体感染模型中评估了具有缀合抗菌剂的纳米载体可消除致病性生物膜
DOI：
10.1016/j.actbio.2018.08.038
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发表时间：
2018-10-01
影响因子：
9.7
通讯作者：
Busscher, Henk J.
中科院分区：
文献类型：
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作者：
Liu, Yong;Ren, Yijin;Busscher, Henk J.
由于多重耐药（MDR）病原体的出现，常规抗微生物剂对于治疗细菌感染变得越来越无效。此外，感染细菌的生物膜生长模式阻碍了抗菌剂在生物膜中的渗透。在这里，我们报告的聚（乙撑）二醇-聚（（β-氨基酯）（PEG-PAE）胶束与共轭抗菌剂，可以独特地穿透生物膜，靶向自己的细菌细胞表面，一旦在低pH值的环境中的生物膜和释放共轭抗菌剂通过降解其酯键与PAE由细菌脂肪酶。在体外，PEG-PAE胶束与共轭三氯生（PEG-PAE-三氯生）产生了无意中泄漏的抗菌货物和更好地杀死MDR金黄色葡萄球菌，大肠杆菌和口腔链球菌生物膜比三氯生溶液。在小鼠中，含有结合三氯生的PEG-PAE-三氯生胶束对MDR S产生了更好的根除效果。与溶液中的三氯生和三氯生负载胶束在相等的三氯生等效浓度下相比，金黄色葡萄球菌感染。将从正畸患者收集的多物种口腔生物膜离体暴露于PEG-PAE-三氯生胶束，证明在三氯生等效浓度比溶液中三氯生低30-40倍的情况下有效杀灭细菌。重要的是，变形链球菌，龋齿的主要致病微生物，优先被PEG-PAE-三氯生胶束杀死。因此，PEG-PAE-三氯生胶束提出了一个有前途的补充，以减少可用的医疗设施，以打击感染在身体的不同situation.Statement的显着性pH适应性聚合物胶束与共轭抗菌剂可以有效地消除感染性生物膜从不同的身体部位在小鼠和男人。通过酯键将抗微生物剂缀合至聚（乙二醇）（PEG）/聚（β-氨基酯）嵌段共聚物以产生胶束纳米载体。疏水性的聚（（β-氨基酯）内核和亲水性的PEG外壳形成稳定的胶束结构。由此形成的PEG-PAE-三氯生胶束不会通过血液循环损失其在感染部位的抗菌物质，而是渗透并积累在生物膜中，一旦进入生物膜内，通过细菌脂肪酶降解其酯键而释放抗菌剂，以杀死生物膜嵌入的细菌。在比应用于溶液时更低的抗菌剂浓度下。PEG-PAE-三氯生胶束可分别在小鼠和人体内有效消除多重耐药病原体和口腔细菌的生物膜，最显著的是高度致龋的变形链球菌，并具有出色的临床转化可能性。(C)2018 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Conventional antimicrobials are becoming increasingly ineffective for treating bacterial infection due to the emergence of multi-drug resistant (MDR) pathogens. In addition, the biofilm-mode-of-growth of infecting bacteria impedes antimicrobial penetration in biofilms. Here, we report on poly(ethylene)gly col-poly((beta-amino esters) (PEG-PAE) micelles with conjugated antimicrobials, that can uniquely penetrate biofilms, target themselves to bacterial cell surfaces once inside the low-pH environment of a biofilm and release conjugated antimicrobials through degradation of their ester-linkage with PAE by bacterial lipases. In vitro, PEG-PAE micelles with conjugated Triclosan (PEG-PAE-Triclosan) yielded no inadvertent leakage of their antimicrobial cargo and better killing of MDR Staphylococcus aureus, Escherichia coli and oral streptococcal biofilms than Triclosan in solution. In mice, PEG-PAE-Triclosan micelles with conjugated Triclosan yielded better eradication efficacy towards a MDR S. aureus-infection compared with Triclosan in solution and Triclosan-loaded micelles at equal Triclosan-equivalent concentrations. Ex vivo exposure of multi-species oral biofilms collected from orthodontic patients to PEG-PAE-Triclosan micelles, demonstrated effective bacterial killing at 30-40 fold lower Triclosan-equivalent concentrations than achieved by Triclosan in solution. Importantly, Streptococcus mutans, the main causative organism of dental caries, was preferentially killed by PEG-PAE-Triclosan micelles. Thus PEG-PAE-Triclosan micelles present a promising addendum to the decreasing armamentarium available to combat infection in diverse sites of the body.Statement of SignificancepH-adaptive polymeric micelles with conjugated antimicrobials can efficiently eradicate infectious biofilms from diverse body sites in mice and men. An antimicrobial was conjugated through an ester-linkage to a poly(ethylene glycol) (PEG)/poly(beta-amino ester) block copolymer to create micellar nanocarriers. Stable micelle structures were formed by the hydrophobic poly((beta-amino ester) inner core and a hydrophilic PEG outer shell. Thus formed PEG-PAE-Triclosan micelles do not lose their antimicrobial cargo underway to an infection site through the blood circulation, but penetrate and accumulate in biofilms to release antimicrobials once inside a biofilm through degradation of its ester-linkage by bacterial lipases, to kill biofilm-embedded bacteria at lower antimicrobial concentrations than when applied in solution. PEG-PAE-Triclosan micelles effectively eradicate biofilms of multi-drug-resistant pathogens and oral bacteria, most notably highly cariogenic Streptococcus mutans, in mice and men respectively, and possess excellent clinical translation possibilities. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.