Targeted Delivery of Narrow-Spectrum Protein Antibiotics to the Lower Gastrointestinal Tract in a Murine Model of Escherichia coli Colonization.
Targeted Delivery of Narrow-Spectrum Protein Antibiotics to the Lower Gastrointestinal Tract in a Murine Model of Escherichia coli Colonization.
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DOI：
10.3389/fmicb.2021.670535
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发表时间：
2021
影响因子：
5.2
通讯作者：
Walker D
中科院分区：
文献类型：
--
作者：
Carpena N;Richards K;Bello Gonzalez TDJ;Bravo-Blas A;Housden NG;Gerasimidis K;Milling SWF;Douce G;Malik DJ;Walker D
细菌素是一种窄谱蛋白质抗生素，可能被用来设计人类肠道微生物区系。然而，在临床前动物模型中，目前缺乏将蛋白质定向输送到下胃肠道(GI)的技术。在这项工作中，我们开发了以细菌素、结肠素E9和Ia为靶点的大肠杆菌微胶囊化方法，在pH响应的配方中，以允许它们在体内定植的小鼠模型中靶向递送和控制释放。采用膜乳化法制备油包水乳状液，再与水溶性聚合物进行交联制得水凝胶微胶囊。微胶囊的制造工艺可以控制药物输送系统的大小，并使微囊治疗货物的产量接近100%。广泛使用的pH响应型阴离子共聚物与藻酸盐生物聚合物相结合，实现了pH引发的胶囊化粘菌素的释放。用小鼠大肠杆菌肠道定植模型进行的活体实验表明，口服胶囊化粘连素可显著减少肠道定植和减少动物粪便中的大肠杆菌排泄量。采用如本文所述的控释药物传递系统对于能够传递新的蛋白质疗法或其他生物干预措施以在感染的小动物模型中进行测试是至关重要的。这种方法可能对未来制定设计人类肠道微生物区系的战略具有相当大的价值，而肠道微生物区系是健康和疾病的核心。
Bacteriocins are narrow-spectrum protein antibiotics that could potentially be used to engineer the human gut microbiota. However, technologies for targeted delivery of proteins to the lower gastrointestinal (GI) tract in preclinical animal models are currently lacking. In this work, we have developed methods for the microencapsulation of Escherichia coli targeting bacteriocins, colicin E9 and Ia, in a pH responsive formulation to allow their targeted delivery and controlled release in an in vivo murine model of E. coli colonization. Membrane emulsification was used to produce a water-in-oil emulsion with the water-soluble polymer subsequently cross-linked to produce hydrogel microcapsules. The microcapsule fabrication process allowed control of the size of the drug delivery system and a near 100% yield of the encapsulated therapeutic cargo. pH-triggered release of the encapsulated colicins was achieved using a widely available pH-responsive anionic copolymer in combination with alginate biopolymers. In vivo experiments using a murine E. coli intestinal colonization model demonstrated that oral delivery of the encapsulated colicins resulted in a significant decrease in intestinal colonization and reduction in E. coli shedding in the feces of the animals. Employing controlled release drug delivery systems such as that described here is essential to enable delivery of new protein therapeutics or other biological interventions for testing within small animal models of infection. Such approaches may have considerable value for the future development of strategies to engineer the human gut microbiota, which is central to health and disease.
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影响因子：
3.2
作者：
Padmanabhan P;Grosse J;Asad AB;Radda GK;Golay X
通讯作者：
Golay X
影响因子：
6.7
作者：
Nedialkova LP;Denzler R;Koeppel MB;Diehl M;Ring D;Wille T;Gerlach RG;Stecher B
通讯作者：
Stecher B
影响因子：
3.3
作者：
McConnell, Emma L.;Basit, Abdul W.;Murdan, Suclaxshina
通讯作者：
Murdan, Suclaxshina
影响因子：
4.6
作者：
McCaughey LC;Ritchie ND;Douce GR;Evans TJ;Walker D
通讯作者：
Walker D
影响因子：
3.1
作者：
WADOLKOWSKI, EA;LAUX, DC;COHEN, PS
通讯作者：
COHEN, PS