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Published March 2015 | Published + Supplemental Material
Journal Article Open

The Ferrous Iron-Responsive BqsRS Two-Component System Activates Genes That Promote Cationic Stress Tolerance


The physiological resistance of pathogens to antimicrobial treatment is a severe problem in the context of chronic infections. For example, the mucus-filled lungs of cystic fibrosis (CF) patients are readily colonized by diverse antibiotic-resistant microorganisms, including Pseudomonas aeruginosa. Previously, we showed that bioavailable ferrous iron [Fe(II)] is present in CF sputum at all stages of infection and constitutes a significant portion of the iron pool at advanced stages of lung function decline [R. C. Hunter et al., mBio 4(4):e00557-13, 2013]. P. aeruginosa, a dominant CF pathogen, senses Fe(II) using a two-component signal transduction system, BqsRS, which is transcriptionally active in CF sputum [R. C. Hunter et al., mBio 4(4):e00557-13, 2013; N. N. Kreamer, J. C. Wilks, J. J. Marlow, M. L. Coleman, and D. K. Newman, J Bacteriol 194:1195–1204, 2012]. Here, we show that an RExxE motif in BqsS is required for BqsRS activation. Once Fe(II) is sensed, BqsR binds a tandem repeat DNA sequence, activating transcription. The BqsR regulon—defined through iterative bioinformatic predictions and experimental validation—includes several genes whose products are known to drive antibiotic resistance to aminoglycosides and polymyxins. Among them are genes encoding predicted determinants of polyamine transport and biosynthesis. Compared to the wild type, bqsS and bqsR deletion mutants are sensitive to high levels of Fe(II), produce less spermidine in high Fe(II), and are more sensitive to tobramycin and polymyxin B but not arsenate, chromate, or cefsulodin. BqsRS thus mediates a physiological response to Fe(II) that guards the cell against positively charged molecules but not negatively charged stressors. These results suggest Fe(II) is an important environmental signal that, via BqsRS, bolsters tolerance of a variety of cationic stressors, including clinically important antimicrobial agents.

Additional Information

© 2015 Kreamer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. Received 23 December 2014; Accepted 7 January 2015; Published 24 February 2015. We thank Megan Bergkessel, other members of the Newman laboratory, and anonymous reviewers for constructive comments on the manuscript. This work was supported by grants to D.K.N. from the Howard Hughes Medical Institute (HHMI) and the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL117328) and by the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology. D.K.N. is an HHMI Investigator.

Attached Files

Published - mBio-2015-Kreamer-.pdf

Supplemental Material - mbo001152185s1.pdf

Supplemental Material - mbo001152185sd1.pdf

Supplemental Material - mbo001152185sd2.pdf

Supplemental Material - mbo001152185sd3.pdf

Supplemental Material - mbo001152185sf1.tiff

Supplemental Material - mbo001152185sf2.tiff

Supplemental Material - mbo001152185sf3.tiff

Supplemental Material - mbo001152185sf4.tiff

Supplemental Material - mbo001152185st1.pdf

Supplemental Material - mbo001152185st2.pdf


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August 22, 2023
August 22, 2023