Research Article: Identification of Pseudomonas aeruginosa Phenazines that Kill Caenorhabditis elegans

Date Published: January 3, 2013

Publisher: Public Library of Science

Author(s): Brent Cezairliyan, Nawaporn Vinayavekhin, Daniel Grenfell-Lee, Grace J. Yuen, Alan Saghatelian, Frederick M. Ausubel, David S. Schneider.


Pathogenic microbes employ a variety of methods to overcome host defenses, including the production and dispersal of molecules that are toxic to their hosts. Pseudomonas aeruginosa, a Gram-negative bacterium, is a pathogen of a diverse variety of hosts including mammals and the nematode Caenorhabditis elegans. In this study, we identify three small molecules in the phenazine class that are produced by P. aeruginosa strain PA14 that are toxic to C. elegans. We demonstrate that 1-hydroxyphenazine, phenazine-1-carboxylic acid, and pyocyanin are capable of killing nematodes in a matter of hours. 1-hydroxyphenazine is toxic over a wide pH range, whereas the toxicities of phenazine-1-carboxylic acid and pyocyanin are pH-dependent at non-overlapping pH ranges. We found that acidification of the growth medium by PA14 activates the toxicity of phenazine-1-carboxylic acid, which is the primary toxic agent towards C. elegans in our assay. Pyocyanin is not toxic under acidic conditions and 1-hydroxyphenazine is produced at concentrations too low to kill C. elegans. These results suggest a role for phenazine-1-carboxylic acid in mammalian pathogenesis because PA14 mutants deficient in phenazine production have been shown to be defective in pathogenesis in mice. More generally, these data demonstrate how diversity within a class of metabolites could affect bacterial toxicity in different environmental niches.

Partial Text

The Gram-negative bacterium Pseudomonas aeruginosa, a pathogen of both plants and metazoans, is a prevalent and pernicious pathogen in persons who are immunocompromised or suffer from cystic fibrosis (CF) [1], [2]. P. aeruginosa employs many mechanisms to antagonize its hosts, including the production of low molecular weight toxins [3], [4], [5]. Identifying toxins, the conditions under which they are produced, and the mechanisms by which they act, are of fundamental importance in understanding and combating the virulence of this clinically-important pathogen.

Pathogenesis of P. aeruginosa can occur through a variety of mechanisms including the production and excretion of toxins. In this study we identified three phenazine toxins produced by P. aeruginosa PA14 that can kill C. elegans under different environmental conditions. We showed that under the conditions of our assay phenazine-1-carboxylic acid is the predominant toxic phenazine produced by P. aeruginosa PA14 that kills C. elegans. Our work suggests that phenazine-1-carboxylic acid should be further studied as a potentially important contributor to toxin-mediated pathogenesis in other metazoan hosts besides C. elegans, including mammals.




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