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 |
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| 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 > School of Infection & Immunity |
| 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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