Identification of Pseudomonas aeruginosa Phenazines that Kill Caenorhabditis elegans

Stanford University, United States of America
PLoS Pathogens (Impact Factor: 8.06). 01/2013; 9(1):e1003101. DOI: 10.1371/journal.ppat.1003101
Source: PubMed

ABSTRACT 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.

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Available from: Grace Yuen, Mar 08, 2014
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    • "The diversity of toxic molecules produced and released by P. aeruginosa facilitates its pathogenicity and contributes to impair lung function in CF. Cezairliyan et al. (2013) Zebrafish embryos The T3SS, biofilm formation and quorum-sensing systems are involved in virulence, and these systems correlate with increased P. aeruginosa virulence in murine models and in humans. Clatworthy et al. (2009) Zebrafish embryos Helped to support a connection between the cystic fibrosis transmembrane conductance regulator (CFTR) and the innate immune response. "
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    Frontiers in Microbiology 02/2015; 6:38. DOI:10.3389/fmicb.2015.00038 · 3.94 Impact Factor
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    • "In contrast, the fast killing assay results in C. elegans death within a period of hours. While the fast killing assay does not require live bacteria and is due to the production of secreted toxins including phenazines (Cezairliyan et al., 2013), the slow killing pathway requires ingestion of live bacteria and many different virulence genes (Feinbaum et al., 2012). P. aeruginosa has been shown to survive ingestion, colonize within an extracellular matrix in the nematode lumen, and cause much less damage to the intestinal epithelial barrier than S. aureus (Sifri, Begun & Ausubel, 2005; Irazoqui et al., 2010). "
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    PeerJ 08/2014; DOI:10.7717/peerj.521 · 2.10 Impact Factor
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    • "We therefore tested whether acs-3 and nhr-25 mutants were generally pathogen sensitive, or whether they exhibited any specificity. We first tested sensitivity to the Gram-negative bacterial pathogen Pseudomonas aeruginosa strain PA14, which kills animals through either toxin production (fast killing) or intestinal infection (slow killing) [34], [35]. acs-3 mutants exhibited a WT sensitivity to P. aeruginosa in a slow killing assay (Figure 4B, Table S8B), whereas nhr-25(ku217) mutants were hypersensitive relative to WT animals (Figure 3B, Table S8B). "
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    PLoS ONE 03/2014; 9(3):e92552. DOI:10.1371/journal.pone.0092552 · 3.23 Impact Factor
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