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Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus
- Source :
- Chemistry & Biology. 22(6):785-792
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- SummaryBacterial infections associated with methicillin-resistant Staphylococcus aureus (MRSA) are a major economic burden to hospitals, and confer high rates of morbidity and mortality among those infected. Exploitation of novel therapeutic targets is thus necessary to combat this dangerous pathogen. Here, we report on the identification and characterization, including crystal structures, of two nitric oxide synthase (NOS) inhibitors that function as antimicrobials against MRSA. These data provide the first evidence that bacterial NOS (bNOS) inhibitors can work synergistically with oxidative stress to enhance MRSA killing. Crystal structures show that each inhibitor contacts an active site Ile residue in bNOS that is Val in the mammalian NOS isoforms. Mutagenesis studies show that the additional nonpolar contacts provided by the Ile in bNOS contribute to tighter binding toward the bacterial enzyme.
- Subjects :
- Methicillin-Resistant Staphylococcus aureus
Cell Survival
Clinical Biochemistry
medicine.disease_cause
Biochemistry
Article
Microbiology
Cell Line
03 medical and health sciences
Mice
Bacterial Proteins
Drug Discovery
medicine
Animals
Protein Isoforms
Binding site
Enzyme Inhibitors
Databases, Protein
Pathogen
Molecular Biology
030304 developmental biology
chemistry.chemical_classification
Pharmacology
0303 health sciences
Binding Sites
biology
030306 microbiology
Mutagenesis
General Medicine
biochemical phenomena, metabolism, and nutrition
Antimicrobial
bacterial infections and mycoses
Methicillin-resistant Staphylococcus aureus
3. Good health
Nitric oxide synthase
Molecular Docking Simulation
Kinetics
Enzyme
chemistry
Staphylococcus aureus
biology.protein
Molecular Medicine
Nitric Oxide Synthase
Protein Binding
Subjects
Details
- ISSN :
- 10745521
- Volume :
- 22
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Chemistry & Biology
- Accession number :
- edsair.doi.dedup.....927db1ffe922cffd89b5ef47a85c96d7
- Full Text :
- https://doi.org/10.1016/j.chembiol.2015.05.013