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Targeted delivery of narrow-spectrum protein antibiotics to the lower gastrointestinal tract in a murine model of Escherichia coli colonization

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journal contribution
posted on 08.11.2021, 11:38 by Nuria Carpena, Kerry Richards, Teresita DJ Bello Gonzalez, Alberto Bravo-Blas, Nicholas G Housden, Konstantinos Gerasimidis, Simon WF Milling, Gillian Douce, Danish MalikDanish Malik, Daniel Walker
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.

Funding

Tackling Antimicrobial Resistance: An Interdisciplinary Approach

Engineering and Physical Sciences Research Council

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Scottish Enterprise (Grant No. PS7305CA55)

MRC (Grant No. MC_PC_15039)

Wellcome Trust (Grant No. 201505/Z/16/Z)

History

School

  • Aeronautical, Automotive, Chemical and Materials Engineering

Department

  • Chemical Engineering

Published in

Frontiers in Microbiology

Volume

12

Publisher

Frontiers Media SA

Version

VoR (Version of Record)

Rights holder

© The authors

Publisher statement

This is an Open Access Article. It is published by Frontiers Media under the Creative Commons Attribution 4.0 Unported Licence (CC BY). Full details of this licence are available at: http://creativecommons.org/licenses/by/4.0/

Acceptance date

21/09/2021

Publication date

2021-10-14

Copyright date

2021

eISSN

1664-302X

Language

en

Depositor

Deposit date: 5 November 2021

Article number

670535