Abstract

Staphylococcus aureus, a Gram-positive bacterium, exhibits many defense mechanisms against the host innate immune system and multiple antibiotics. Staphylococcus aureus is second only to Clostridium difficile as a cause of healthcare-associated infections in the United States; therefore, it is important to develop new therapeutics. The exposure of bacterial pathogens to nitric oxide (NO·), an immune effector, causes growth inhibition and induction of stress regulons. Staphylococcus aureus, however, has evolved defense mechanisms to resist NO·. The metabolic resistance of S.aureus to NO· is one of the adaptations that makes it unique and more pathogenic than other Staphylococcal species such as S. epidermidis and S. saprophyticus. In a previous transposon-sequencing (Tn-seq) study using a strain of a community-acquired methicillin-resistant S.aureus (USA300 LAC), 168 genes were identified as likely to play a role in NO· resistance. One of these genes, encoding MarR-family transcriptional regulator mgrA, was investigated in this research with the goal of better understanding the control of gene expression during nitrosative stress. A deletion mutant of the gene, ΔmgrA, was constructed and investigated to elucidate its phenotype in the presence of NO·. The mutant was also investigated during peroxide (oxidative) stress, because potentiation of oxidative stress is one of the major ways NO· impacts bacteria. Although the previous Tn-seq data suggested that MgrA is required for NO· resistance, our data revealed that the ΔmgrA mutant exhibited enhanced NO· resistance relative to wildtype, but not peroxide resistance. This suggests that MgrA regulates genes associated with specific aspects of NO· stress that are separate from oxidative stress. Further studies will investigate what genes MgrA regulates during NO· stress and whether these could represent potential antibiotic targets.

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