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The ability to switch to heme as an iron source and away from siderophore uptake provides an advantage in chronic infection. We have recently shown the extracellular heme metabolites biliverdin IX\u03b2 (BVIX\u03b2) and BVIX\u03b4 positively regulate the heme-dependent cell surface signaling cascade. We further investigated the role of BVIX\u03b2 and BVIX\u03b4 in cell signaling utilizing allelic strains lacking a functional heme oxygenase (\n              <jats:italic>hemO<\/jats:italic>\n              in) or one reengineered to produce BVIX\u03b1 (\n              <jats:italic>hemO<\/jats:italic>\n              \u03b1). Compared to PAO1, both strains show a heme-dependent growth defect, decreased swarming and twitching, and less robust biofilm formation. Interestingly, the motility and biofilm defects were partially rescued on addition of exogenous BVIX\u03b2 and BVIX\u03b4. Utilizing liquid chromatography-tandem mass spectrometry, we performed a comparative proteomics and metabolomics analysis of PAO1 versus the allelic strains in shaking and static conditions. In shaking conditions, the\n              <jats:italic>hemO<\/jats:italic>\n              allelic strains showed a significant increase in proteins involved in quorum sensing, phenazine production, and chemotaxis. Metabolite profiling further revealed increased levels of\n              <jats:italic>Pseudomonas<\/jats:italic>\n              quinolone signal and phenazine metabolites. In static conditions, we observed a significant repression of chemosensory pathways and type IV pili biogenesis proteins as well as several phosphodiesterases associated with biofilm dispersal. We propose BVIX metabolites function as signaling and chemotactic molecules integrating heme utilization as an iron source into the adaptation of\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              from a planktonic to sessile lifestyle.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              The opportunistic pathogen\n              <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n              causes long-term chronic infection in the airways of cystic fibrosis patients. The ability to scavenge iron and to establish chronic infection within this environment coincides with a switch to utilize heme as the primary iron source. Herein, we show the heme metabolites biliverdin beta and delta are themselves important signaling molecules integrating the switch in iron acquisition systems with cooperative behaviors such as motility and biofilm formation that are essential for long-term chronic infection. These significant findings will enhance the development of viable multi-targeted therapeutics effective against both heme utilization and cooperative behaviors essential for survival and persistence within the host.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.02763-23","type":"journal-article","created":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T14:00:49Z","timestamp":1707228049000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["<i>Pseudomonas aeruginosa<\/i>\n            heme metabolites biliverdin IX\u03b2 and IX\u03b4 are integral to lifestyle adaptations associated with chronic infection"],"prefix":"10.1128","volume":"15","author":[{"given":"Saba","family":"Shahzad","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 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