OxyR regulates the transcriptional response to hydrogen peroxide.

is a Gram-negative opportunistic pathogen that causes diverse infections, including pneumonia, bacteremia, and wound infections. Due to multiple intrinsic and acquired antimicrobial-resistance mechanisms, isolates are commonly multi-drug resistant and infections are notoriously difficult to treat. The World Health Organization recently highlighted carbapenem-resistant as a 'critical priority' for the development of new antimicrobials because of the risk to human health posed by this organism. Therefore, it is important to discover mechanisms used by to survive stresses encountered during infection in order to identify new drug targets. In this study, we identified hydrogen peroxide (HO) as a stressor produced in the lung during infection using imaging and defined OxyR as a transcriptional regulator of the HO stress response. Upon exposure to HO, differentially transcribes several hundred genes. However, transcriptional upregulation of genes predicted to detoxify hydrogen peroxide is abolished in genetically inactivated for the transcriptional regulator Moreover, inactivation of in both antimicrobial-susceptible and multi-drug-resistant strains impairs growth in the presence of HO OxyR is a direct regulator of and which encode the major HO-degrading enzymes in , as confirmed through measurement of promoter binding by recombinant OxyR in electromobility shift assays. Finally, an mutant is less fit than wild-type during infection of the murine lung. This work reveals a mechanism used by this important human pathogen to survive HO stress encountered during infection.