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      Characteristics of the Clostridium difficile cell envelope and its importance in therapeutics

      review-article
      1 , 1 , 1 ,
      Microbial Biotechnology
      John Wiley and Sons Inc.

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          Summary

          Clostridium difficile infection ( CDI) is a challenging threat to human health. Infections occur after disruption of the normal microbiota, most commonly through the use of antibiotics. Current treatment for CDI largely relies on the broad‐spectrum antibiotics vancomycin and metronidazole that further disrupt the microbiota resulting in frequent recurrence, highlighting the need for C. difficile‐specific antimicrobials. The cell surface of C. difficile represents a promising target for the development of new drugs. C. difficile possesses a highly deacetylated peptidoglycan cell wall containing unique secondary cell wall polymers. Bound to the cell wall is an essential S‐layer, formed of SlpA and decorated with an additional 28 related proteins. In addition to the S‐layer, many other cell surface proteins have been identified, including several with roles in host colonization. This review aims to summarize our current understanding of these different C. difficile cell surface components and their viability as therapeutic targets.

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          Most cited references94

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          Peptidoglycan structure and architecture.

          The peptidoglycan (murein) sacculus is a unique and essential structural element in the cell wall of most bacteria. Made of glycan strands cross-linked by short peptides, the sacculus forms a closed, bag-shaped structure surrounding the cytoplasmic membrane. There is a high diversity in the composition and sequence of the peptides in the peptidoglycan from different species. Furthermore, in several species examined, the fine structure of the peptidoglycan significantly varies with the growth conditions. Limited number of biophysical data on the thickness, elasticity and porosity of peptidoglycan are available. The different models for the architecture of peptidoglycan are discussed with respect to structural and physical parameters.
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            Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis.

            Building and maintaining a homeostatic relationship between a host and its colonizing microbiota entails ongoing complex interactions between the host and the microorganisms. The mucosal immune system, including epithelial cells, plays an essential part in negotiating this equilibrium. Paneth cells (specialized cells in the epithelium of the small intestine) are an important source of antimicrobial peptides in the intestine. These cells have become the focus of investigations that explore the mechanisms of host-microorganism homeostasis in the small intestine and its collapse in the processes of infection and chronic inflammation. In this Review, we provide an overview of the intestinal microbiota and describe the cell biology of Paneth cells, emphasizing the composition of their secretions and the roles of these cells in intestinal host defence and homeostasis. We also highlight the implications of Paneth cell dysfunction in susceptibility to chronic inflammatory bowel disease.
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              Clostridium difficile infection

              Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis - the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota.
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                Author and article information

                Contributors
                r.fagan@sheffield.ac.uk
                Journal
                Microb Biotechnol
                Microb Biotechnol
                10.1111/(ISSN)1751-7915
                MBT2
                Microbial Biotechnology
                John Wiley and Sons Inc. (Hoboken )
                1751-7915
                17 June 2016
                January 2017
                : 10
                : 1 ( doiID: 10.1111/mbt2.2017.10.issue-1 )
                : 76-90
                Affiliations
                [ 1 ] Krebs Institute Department of Molecular Biology and BiotechnologyUniversity of Sheffield Sheffield S10 2TNUK
                Author notes
                [*] [* ]For correspondence. E‐mail r.fagan@ 123456sheffield.ac.uk ; Tel. (+44) 114 222 4182; Fax (+44) 114 222 2787.
                [†]

                Authors contributed equally to this review.

                Author information
                http://orcid.org/0000-0002-8704-4828
                Article
                MBT212372
                10.1111/1751-7915.12372
                5270738
                27311697
                0f7d6676-f927-486c-8ddc-83c8ca26b7b7
                © 2016 The Authors. Microbial Biotechnology published by Society for Applied Microbiology and John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 31 March 2016
                : 26 May 2016
                : 30 May 2016
                Page count
                Figures: 3, Tables: 1, Pages: 15, Words: 10406
                Funding
                Funded by: UK Medical Research Council
                Award ID: MR/N000900/1
                Funded by: Society for Applied Microbiology
                Funded by: AvidBiotics Corp
                Funded by: University of Sheffield
                Categories
                Minireview
                Minireviews
                Custom metadata
                2.0
                mbt212372
                January 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.3 mode:remove_FC converted:27.01.2017

                Biotechnology
                Biotechnology

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