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JAC Advance Access published online on May 24, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki177
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received January 4, 2005
Revised February 28, 2005
Accepted April 26, 2005

Original article

Treatment of experimental Escherichia coli infection with recombinant bacteriophage-derived capsule depolymerase

Naseem Mushtaq 1, Maria B. Redpath 1, J. Paul Luzio 2, and Peter W. Taylor 1*

1 Microbiology Group, School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK
2 Cambridge Institute for Medical Research and Department of Clinical Biochemistry, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK

* To whom correspondence should be addressed.
Peter W. Taylor, E-mail: peter.taylor{at}ulsop.ac.uk


  Abstract

Objectives: The aim of this study was to investigate the effect of single doses of the capsule depolymerizing enzyme endosialidase E (endoE) on the course of systemic infection due to Escherichia coli K1 strains in neonatal rats. We also determined the capacity of the enzyme to increase the sensitivity of K1 strains to rat peritoneal macrophages.

Methods: Bacteraemia was established in Wistar rats by induction of gastrointestinal colonization with the virulent K1 strain A192PP; colonization preceded a lethal bacteraemia. Decreasing single doses of endoE were administered intraperitoneally. Macrophage engulfment of K1 strain A192PP was evaluated by staining and microscopy in the presence and absence of endoE.

Results: A192PP colonized the gastrointestinal tract of all 2-day-old animals and produced bacteraemia in over 90%. A single endoE dose of 0.25 µg curtailed bacteraemia and prevented death in at least 80% of infected animals. Older animals (up to 5 days of age) were less susceptible to systemic infection following intestinal colonization. EndoE-mediated removal of K1 capsular polysaccharide led to increased ingestion by macrophages.

Conclusions: A small single dose of capsule-depolymerizing enzyme has therapeutic utility in lethal systemic infection in a non-invasive model that has characteristics of the infectious process in humans. We propose that the enzyme reduces the virulence of E. coli K1 by rapid removal of the protective capsular polysaccharide, sensitizing the pathogen to host defences such as phagocytosis by macrophages. Thus, whilst endoE-mediated therapy may not be a viable approach to the treatment of systemic infection in humans, it does support the concept that alteration of the cell wall phenotype is a valid therapeutic strategy.

Keywords: bacteraemia; endosialidase; phenotype modification; polysaccharide capsule; enzyme therapy.
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