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

Laura C. McCaughey, Inokentijs Josts, Rhys Grinter, Paul White, Olwyn Byron, Nicholas P. Tucker, Jacqueline M. Matthews, Colin Kleanthous, Cynthia B. Whitchurch, Daniel Walker

Research output: Contribution to journalArticle

12 Citations (Scopus)

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, from where it can efficiently locate its outer membrane receptor FpvAI. This strategy of utilising 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 support the development of pyocin SD2 as a therapeutic in its own right.

LanguageEnglish
Pages2345-2358
Number of pages14
JournalBiochemical Journal
Volume473
Issue number15
DOIs
Publication statusPublished - 28 Jul 2016

Fingerprint

Pyocins
Pseudomonas aeruginosa
Anti-Bacterial Agents
Proteins
Membranes
Polysaccharides
Antigens
Pathogens
Microbial Drug Resistance

Keywords

  • antibiotic resistance
  • Pseudomonas aeruginosa
  • antibiotic development
  • pyocins
  • pyocin SD2
  • anti‐ pseudomonal therapeutics

Cite this

McCaughey, Laura C. ; Josts, Inokentijs ; Grinter, Rhys ; White, Paul ; Byron, Olwyn ; Tucker, Nicholas P. ; Matthews, Jacqueline M. ; Kleanthous, Colin ; Whitchurch, Cynthia B. ; Walker, Daniel. / Discovery, characterisation and in vivo activity of pyocin SD2, a protein antibiotic from Pseudomonas aeruginosa. In: Biochemical Journal. 2016 ; Vol. 473, No. 15. pp. 2345-2358.
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McCaughey, LC, Josts, I, Grinter, R, White, P, Byron, O, Tucker, NP, Matthews, JM, Kleanthous, C, Whitchurch, CB & Walker, D 2016, 'Discovery, characterisation and in vivo activity of pyocin SD2, a protein antibiotic from Pseudomonas aeruginosa' Biochemical Journal, vol. 473, no. 15, pp. 2345-2358. https://doi.org/10.1042/BCJ20160470

Discovery, characterisation and in vivo activity of pyocin SD2, a protein antibiotic from Pseudomonas aeruginosa. / McCaughey, Laura C.; Josts, Inokentijs; Grinter, Rhys; White, Paul; Byron, Olwyn; Tucker, Nicholas P.; Matthews, Jacqueline M.; Kleanthous, Colin; Whitchurch, Cynthia B.; Walker, Daniel.

In: Biochemical Journal, Vol. 473, No. 15, 28.07.2016, p. 2345-2358.

Research output: Contribution to journalArticle

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AU - Tucker, Nicholas P.

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