Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 25, Pages E3538-E3547Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1600424113
Keywords
phenazine; RND efflux; MexGHI-OpmD; biofilm; antibiotic
Categories
Funding
- IGERT Fellowship [0801530]
- Amgen Scholars Program at Columbia University/Barnard College
- Chinese Scholarship Council
- NSF [1353553]
- NIH [R01AI103369, R01GM108492, R01AI091702]
- NIH
- Columbia University's Bridge Program
- Division Of Graduate Education
- Direct For Education and Human Resources [0801530] Funding Source: National Science Foundation
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1353553] Funding Source: National Science Foundation
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Redox-cycling compounds, including endogenously produced phenazine antibiotics, induce expression of the efflux pump MexGHI-OpmD in the opportunistic pathogen Pseudomonas aeruginosa. Previous studies of P. aeruginosa virulence, physiology, and biofilm development have focused on the blue phenazine pyocyanin and the yellow phenazine-1-carboxylic acid (PCA). In P. aeruginosa phenazine biosynthesis, conversion of PCA to pyocyanin is presumed to proceed through the intermediate 5-methylphenazine-1-carboxylate (5-Me-PCA), a reactive compound that has eluded detection in most laboratory samples. Here, we apply electrochemical methods to directly detect 5-Me-PCA and find that it is transported by MexGHI-OpmD in P. aeruginosa strain PA14 planktonic and biofilm cells. We also show that 5-Me-PCA is sufficient to fully induce MexGHI-OpmD expression and that it is required for wild-type colony biofilm morphogenesis. These physiological effects are consistent with the high redox potential of 5-Me-PCA, which distinguishes it from other well-studied P. aeruginosa phenazines. Our observations highlight the importance of this compound, which was previously overlooked due to the challenges associated with its detection, in the context of P. aeruginosa gene expression and multicellular behavior. This study constitutes a unique demonstration of efflux-based self-resistance, controlled by a simple circuit, in a Gram-negative pathogen.
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