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For example, the mucus-filled lungs of cystic fibrosis (CF) patients are readily colonized by diverse antibiotic-resistant microorganisms, including\n            <jats:named-content content-type=\"genus-species\">Pseudomonas aeruginosa<\/jats:named-content>\n            . 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].\n            <jats:named-content content-type=\"genus-species\">P. aeruginosa<\/jats:named-content>\n            , 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\u20131204, 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\u2014defined through iterative bioinformatic predictions and experimental validation\u2014includes 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,\n            <jats:italic>bqsS<\/jats:italic>\n            and\n            <jats:italic>bqsR<\/jats:italic>\n            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.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Clearing chronic infections is challenging due to the physiological resistance of opportunistic pathogens to antibiotics. Effective treatments are hindered by a lack of understanding of how these organisms survive\n            <jats:italic>in situ<\/jats:italic>\n            . Fe(II) is typically present at micromolar levels in soils and sedimentary habitats, as well as in CF sputum. All P.\u00a0aeruginosa strains possess a two-component system, BqsRS, that specifically senses extracellular Fe(II) at low micromolar concentrations. Our work shows that BqsRS protects the cell against cationic perturbations to the cell envelope as well as low pH and reduction potential (Eh), conditions under which Fe\n            <jats:sup>2+<\/jats:sup>\n            is stable. Fe(II) can thus be understood as a proxy for a broader environmental state; the cellular response to its detection may help rationalize the resistance of P.\u00a0aeruginosa to clinically important cationic antibiotics. This finding demonstrates the importance of considering environmental chemistry when exploring mechanisms of microbial survival in habitats that include the human body.\n          <\/jats:p>","DOI":"10.1128\/mbio.02549-14","type":"journal-article","created":{"date-parts":[[2015,2,26]],"date-time":"2015-02-26T14:43:32Z","timestamp":1424961812000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":54,"title":["The Ferrous Iron-Responsive BqsRS Two-Component System Activates Genes That Promote Cationic Stress Tolerance"],"prefix":"10.1128","volume":"6","author":[{"given":"Naomi N.","family":"Kreamer","sequence":"first","affiliation":[{"name":"Division of Biology and Biological Engineering, Caltech, Pasadena, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Costa","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, Caltech, Pasadena, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianne K.","family":"Newman","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, Caltech, Pasadena, California, USA"},{"name":"Division of Geological and Planetary Sciences, Caltech, Pasadena, California, USA"},{"name":"Howard Hughes Medical Institute, Caltech, Pasadena, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1369-5274(03)00039-0"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio0406-171"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08301"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/0-387-28881-3_1"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504266102"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01473-07"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(00)01913-2"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/ie50614a030"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.05634-11"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01465-12"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00557-13"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200609-1354OC"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.129.5.1148"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.26933-0"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI13870"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084353"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/am.28.6.987-991.1974"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.2136\/sssaj1974.03615995003800010024x"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2008.00135.x"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.4161\/cib.1.1.6717"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01546-10"},{"key":"e_1_3_2_23_2","first-page":"166","article-title":"TMbase\u2014a database of membrane spanning proteins segments","volume":"374","author":"Hofmann K","year":"1993","unstructured":"Hofmann K, Stoffel W. 1993. 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