Acinetobacter baumanniiOxyR Regulates the Transcriptional Response to Hydrogen Peroxide
ABSTRACTAcinetobacter baumanniiis a Gram-negative opportunistic pathogen that causes diverse infections, including pneumonia, bacteremia, and wound infections. Due to multiple intrinsic and acquired antimicrobial-resistance mechanisms,A. baumanniiisolates are commonly multidrug resistant, and infections are notoriously difficult to treat. The World Health Organization recently highlighted carbapenem-resistantA. baumanniias 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 the mechanisms used byA. baumanniito survive stresses encountered during infection in order to identify new drug targets. In this study, by use ofin vivoimaging, we identified hydrogen peroxide (H2O2) as a stressor produced in the lung duringA. baumanniiinfection and defined OxyR as a transcriptional regulator of the H2O2stress response. Upon exposure to H2O2,A. baumanniidifferentially transcribes several hundred genes. However, the transcriptional upregulation of genes predicted to detoxify hydrogen peroxide is abolished in anA. baumanniistrain in which the transcriptional regulatoroxyRis genetically inactivated. Moreover, inactivation ofoxyRin both antimicrobial-susceptible and multidrug-resistantA. baumanniistrains impairs growth in the presence of H2O2. OxyR is a direct regulator ofkatEandahpF1, which encode the major H2O2-degrading enzymes inA. baumannii, as confirmed through measurement of promoter binding by recombinant OxyR in electromobility shift assays. Finally, anoxyRmutant is less fit than wild-typeA. baumanniiduring infection of the murine lung. This work reveals a mechanism used by this important human pathogen to survive H2O2stress encountered during infection.