Staphylococcus aureus is a major human pathogen that causes significant morbidity and mortality in both hospital- and community-acquired infections. The appearance of multidrug-resistant strains has compounded this problem, galvanizing efforts aimed at identifying novel therapeutic targets. One promising area for the development of novel antimicrobials is S. aureus heme metabolism, as this process is vital to staphylococcal pathogenesis. S. aureus acquires heme from hemoglobin to satisfy its nutrient iron requirement. Once heme is internalized, it is enzymatically degraded, resulting in the production of small molecule chromophores with as- yet-undetermined functions in bacteria. Intriguingly, most bacterial pathogens that utilize heme as a nutrient iron source can also synthesize heme through the activity of a dedicated synthesis pathway. Heme synthesis is conserved in virtually all cells, yet the process by which heme synthesis is regulated is largely unknown. We hypothesize that heme catabolites have a critical role in staphylococcal physiology. We also predict that S. aureus heme synthesis is regulated to adjust to the amount of heme and heme catabolites within the cell. Notably, we have discovered a small molecule activator of an enzyme within the heme synthesis pathway and this molecule sensitizes S. aureus to light, establishing a valuable probe to study heme synthesis as well as a candidate molecule for antibiotic development. In this grant application, we propose experiments to test this model.
In Aim 1 we will define the function of heme degradation products in S. aureus.
In Aim 2 we will define the contribution of regulated heme synthesis to staphylococcal pathogenesis. Finally, Aim 3 studies will determine the utility of small molecule-dependent activation of heme synthesis as a molecular tool as well as a candidate therapeutic strategy. Together, these proposed experiments will provide a mechanistic understanding of the coordination of heme synthesis and degradation in S. aureus, and exploit this knowledge to generate candidate antimicrobials with efficacy against numerous Gram positive pathogens.

Public Health Relevance

S. aureus is one of the most significant threats to the public health of the United States. This proposal will provide mechanistic insights into the contribution of regulated heme synthesis and degradation to the pathogenesis of S. aureus infections. Considering that these processes are conserved in virtually all bacterial pathogens, results accrued from these studies will be applicable across a variety of infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI069233-14
Application #
9463343
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Huntley, Clayton C
Project Start
2006-02-01
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Noto, Michael J; Burns, William J; Beavers, William N et al. (2017) Mechanisms of pyocyanin toxicity and genetic determinants of resistance in Staphylococcus aureus. J Bacteriol :
Peng, Hui; Zhang, Yixiang; Palmer, Lauren D et al. (2017) Hydrogen Sulfide and Reactive Sulfur Species Impact Proteome S-Sulfhydration and Global Virulence Regulation in Staphylococcus aureus. ACS Infect Dis 3:744-755
Lojek, Lisa J; Farrand, Allison J; Wisecaver, Jennifer H et al. (2017) Chlamydomonas reinhardtii LFO1 Is an IsdG Family Heme Oxygenase. mSphere 2:
Surdel, Matthew C; Horvath Jr, Dennis J; Lojek, Lisa J et al. (2017) Antibacterial photosensitization through activation of coproporphyrinogen oxidase. Proc Natl Acad Sci U S A 114:E6652-E6659
Peng, Hui; Shen, Jiangchuan; Edmonds, Katherine A et al. (2017) Sulfide Homeostasis and Nitroxyl Intersect via Formation of Reactive Sulfur Species in Staphylococcus aureus. mSphere 2:
Juttukonda, Lillian J; Berends, Evelien T M; Zackular, Joseph P et al. (2017) Dietary Manganese Promotes Staphylococcal Infection of the Heart. Cell Host Microbe 22:531-542.e8
Dutter, Brendan F; Mike, Laura A; Reid, Paul R et al. (2016) Decoupling Activation of Heme Biosynthesis from Anaerobic Toxicity in a Molecule Active in Staphylococcus aureus. ACS Chem Biol 11:1354-61
Choby, Jacob E; Skaar, Eric P (2016) Heme Synthesis and Acquisition in Bacterial Pathogens. J Mol Biol 428:3408-28
Choby, Jacob E; Mike, Laura A; Mashruwala, Ameya A et al. (2016) A Small-Molecule Inhibitor of Iron-Sulfur Cluster Assembly Uncovers a Link between Virulence Regulation and Metabolism in Staphylococcus aureus. Cell Chem Biol 23:1351-1361
Palmer, Lauren D; Skaar, Eric P (2016) Transition Metals and Virulence in Bacteria. Annu Rev Genet 50:67-91

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