TY - JOUR
T1 - Discovery, characterisation and in vivo activity of pyocin SD2, a protein antibiotic from Pseudomonas aeruginosa
AU - McCaughey, Laura C.
AU - Josts, Inokentijs
AU - Grinter, Rhys
AU - White, Paul
AU - Byron, Olwyn
AU - Tucker, Nicholas P.
AU - Matthews, Jacqueline M.
AU - Kleanthous, Colin
AU - Whitchurch, Cynthia B.
AU - Walker, Daniel
N1 - ©2016 The Author(s).
PY - 2016/7/28
Y1 - 2016/7/28
N2 - 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.
AB - 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.
KW - antibiotic resistance
KW - Pseudomonas aeruginosa
KW - antibiotic development
KW - pyocins
KW - pyocin SD2
KW - anti‐ pseudomonal therapeutics
UR - http://www.biochemj.org/
U2 - 10.1042/BCJ20160470
DO - 10.1042/BCJ20160470
M3 - Article
C2 - 27252387
VL - 473
SP - 2345
EP - 2358
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 15
ER -