A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity
Ryan M. Singh,
Sujata S. Chaudhari,
Sasmita Panda,
Elizabeth H. Hutfless,
Cortney E. Heim,
Dhananjay Shinde,
Abdulelah A. Alqarzaee,
Margaret Sladek,
Vineet Kumar,
Matthew C. Zimmerman,
Paul D. Fey,
Tammy Kielian,
Vinai C. Thomas
Affiliations
Ryan M. Singh
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Sujata S. Chaudhari
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Sasmita Panda
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Elizabeth H. Hutfless
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Cortney E. Heim
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Dhananjay Shinde
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Abdulelah A. Alqarzaee
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Margaret Sladek
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Vineet Kumar
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Matthew C. Zimmerman
Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Paul D. Fey
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Tammy Kielian
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA
Vinai C. Thomas
Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA; Corresponding author. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-6495, USA.
Most coagulase-negative staphylococcal species, including the opportunistic pathogen Staphylococcus epidermidis, struggle to maintain redox homeostasis and grow under nitrosative stress. Under these conditions, growth can only resume once nitric oxide (NO) is detoxified by the flavohemoglobin Hmp. Paradoxically, S. epidermidis produces endogenous NO through its genetically encoded nitric oxide synthase (seNOS) and heavily relies on its activity for growth. In this study, we investigate the basis of the growth advantage attributed to seNOS activity. Our findings reveal that seNOS supports growth by countering Hmp toxicity. S. epidermidis relies on Hmp activity for its survival in the host under NO stress. However, in the absence of nitrosative stress, Hmp generates significant amounts of the harmful superoxide radical (O2•-) from its heme prosthetic group which impedes growth. To limit Hmp toxicity, nitrite (NO2−) derived from seNOS promotes CymR-CysK regulatory complex activity, which typically regulates cysteine metabolism, but we now demonstrate to also repress hmp transcription. These findings reveal a critical mechanism through which the bacterial NOS-Hmp axis drives staphylococcal fitness.
