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 Grinter, Mr Rhys and MCCAUGHEY, Dr LAURA and Byron, Professor Olwyn |
| 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 > School of Infection & Immunity 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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