New class of precision antimicrobials redefines role of Clostridium difficile S-layer in virulence and viability

Kirk, J. A., Gebhart, D., Buckley, A. M., Lok, S., Scholl, D., Douce, G. R. , Govoni, G. R. and Fagan, R. P. (2017) New class of precision antimicrobials redefines role of Clostridium difficile S-layer in virulence and viability. Science Translational Medicine, 9(406), eaah6813. (doi: 10.1126/scitranslmed.aah6813) (PMID:28878013) (PMCID:PMC5603275)

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Abstract

There is a medical need for antibacterial agents that do not damage the resident gut microbiota or promote the spread of antibiotic resistance. We recently described a prototypic precision bactericidal agent, Av-CD291.2, which selectively kills specific Clostridium difficile strains and prevents them from colonizing mice. We have since selected two Av-CD291.2-resistant mutants that have a surface (S)-layer-null phenotype due to distinct point mutations in the slpA gene. Using newly identified bacteriophage receptor binding proteins for targeting, we constructed a panel of Avidocin-CDs that kills diverse C. difficile isolates in an S-layer sequence-dependent manner. In addition to bacteriophage receptor recognition, characterization of the mutants also uncovered important roles for S-layer protein A (SlpA) in sporulation, resistance to innate immunity effectors, and toxin production. Surprisingly, S-layer-null mutants were found to persist in the hamster gut despite a complete attenuation of virulence. These findings suggest antimicrobials targeting virulence factors dispensable for fitness in the host force pathogens to trade virulence for viability and would have clear clinical advantages should resistance emerge. Given their exquisite specificity for the pathogen, Avidocin-CDs have substantial therapeutic potential for the treatment and prevention of C. difficile infections.

Item Type:Articles
Additional Information:This work was supported by the National Institute of Allergy and Infectious Diseases of the NIH under award number R21AI121692. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support was obtained from the Medical Research Council (grant number MR/N000900/1 to R.P.F.), AvidBiotics Corp. and the University of Sheffield via the Higher Education Innovation Fund 2011–2015 (to R.P.F.), and the Wellcome Trust (grant number 086418 to G.R.D.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Douce, Dr Gillian and Buckley, Dr Anthony
Authors: Kirk, J. A., Gebhart, D., Buckley, A. M., Lok, S., Scholl, D., Douce, G. R., Govoni, G. R., and Fagan, R. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
ISSN (Online):1946-6242
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Science Translational Medicine 9(406): eaah6813
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
492111Genetic and phenotypic characterisation of emerging virulent Clostridium difficileGillian DouceWellcome Trust (WELLCOTR)086418/B/08/ZIII - BACTERIOLOGY