Discovery, characterization and in vivo activity of pyocin SD2, a protein antibiotic from Pseudomonas aeruginosa

Mccaughey, L. C., Josts, I., Grinter, R., White, P., Byron, O. , Tucker, N. P., Matthews, J. M., Kleanthous, C., Whitchurch, C. and Walker, D. (2016) Discovery, characterization and in vivo activity of pyocin SD2, a protein antibiotic from Pseudomonas aeruginosa. Biochemical Journal, 473(15), pp. 2345-2358. (doi:10.1042/bcj20160470) (PMID:27252387) (PMCID:PMC4964976)

Mccaughey, L. C., Josts, I., Grinter, R., White, P., Byron, O. , Tucker, N. P., Matthews, J. M., Kleanthous, C., Whitchurch, C. and Walker, D. (2016) Discovery, characterization and in vivo activity of pyocin SD2, a protein antibiotic from Pseudomonas aeruginosa. Biochemical Journal, 473(15), pp. 2345-2358. (doi:10.1042/bcj20160470) (PMID:27252387) (PMCID:PMC4964976)

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Abstract

Increasing rates of antibiotic resistance among Gram-negative pathogens such as Pseudomonas aeruginosa means alternative approaches to antibiotic development are urgently required. Pyocins, produced by P. aeruginosa for intraspecies competition, are highly potent protein antibiotics known to actively translocate across the outer membrane of P. aeruginosa. Understanding and exploiting the mechanisms by which pyocins target, penetrate and kill P. aeruginosa is a promising approach to antibiotic development. In this work we show the therapeutic potential of a newly identified tRNase pyocin, pyocin SD2, by demonstrating its activity in vivo in a murine model of P. aeruginosa lung infection. In addition, we propose a mechanism of cell targeting and translocation for pyocin SD2 across the P. aeruginosa outer membrane. Pyocin SD2 is concentrated at the cell surface, via binding to the common polysaccharide antigen (CPA) of P. aeruginosa lipopolysaccharide (LPS), from where it can efficiently locate its outer membrane receptor FpvAI. This strategy of utilizing both the CPA and a protein receptor for cell targeting is common among pyocins as we show that pyocins S2, S5 and SD3 also bind to the CPA. Additional data indicate a key role for an unstructured N-terminal region of pyocin SD2 in the subsequent translocation of the pyocin into the cell. These results greatly improve our understanding of how pyocins target and translocate across the outer membrane of P. aeruginosa. This knowledge could be useful for the development of novel anti-pseudomonal therapeutics and will also support the development of pyocin SD2 as a therapeutic in its own right.

Item Type:Articles
Additional Information:Wellcome Trust grant 106064/Z/14/2 is to the University of Oxford.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Walker, Professor Daniel and Byron, Professor Olwyn and Grinter, Mr Rhys and Mccaughey, Miss Laura
Authors: Mccaughey, L. C., Josts, I., Grinter, R., White, P., Byron, O., Tucker, N. P., Matthews, J. M., Kleanthous, C., Whitchurch, C., and Walker, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Biochemical Journal
Publisher:Portland Press
ISSN:0264-6021
ISSN (Online):1470-8728
Published Online:28 July 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Biochemical Journal 473(15):2345-2358
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
660151Priming Innovative Translational Research - The University of Glasgow Confidence in Concept ProgrammeAnna DominiczakMedical Research Council (MRC)MC_PC_13063RI CARDIOVASCULAR & MEDICAL SCIENCES