Pseudomonas aeruginosa is a ubiquitous, opportunistic pathogen infecting individuals with cystic fibrosis (CF). Due to the uncanny antibiotic resistance, CF patients infected with Pseudomonas often have chronic infections with limited therapeutic options. Part of the ability to resist antibiotic treatment and clearance by the immune system is due to the ability of the organism to grow in a community termed a biofilm. A basic understanding of the pathogenic mechanisms utilized by this organism in a bioflm is needed for possible therapeutic targets. P. aeruginosa produces alginate, rhamnolipids, type IV pili and cyanide under biofilm growth conditions and all of these are controlled by a protein that regulates transcription, AlgR. Iron acquisition is also an important part of establishing and maintaining P. aeruginosa biofilms. In fact, alginate production increases as iron levels decrease. We have recently determined that AlgR phosphorylation controls iron acquisition molecules, termed siderophores. Moreover, we have also determined that AlgR phosphorylation is required in a murine acute pneumonia model. Our preliminary evidence also shows that these multiple phenotypes (twitching motility, alginate and siderophore production) are both oxygen- and AlgR-dependent. Together, these data indicate that the protein that phosphorylates AlgR, AlgZ/FimS, responds to oxygen, phosphorylates AlgR and activates iron acquisition molecules. Therapeutic inhibition of the AlgZR two-component system would shut down alginate production, twitching motility, and iron acquisition. The goals of this research are to determine how AlgZ senses oxygen and to determine which genes are specifically activated by AlgR to control iron acquisition.