title: Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus.
abstract: Bacterial 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.
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA 92697-3900, USA.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Holden
authors.affiliation: Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA.
authors.forename: Soosung
authors.initials: S
authors.lastname: Kang
authors.affiliation: Departments of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093, USA.
authors.forename: Federico C
authors.initials: FC
authors.lastname: Beasley
authors.affiliation: Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA.
authors.forename: Maris A
authors.initials: MA
authors.lastname: Cinelli
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA 92697-3900, USA.
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
authors.forename: Saurabh G
authors.initials: SG
authors.lastname: Roy
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA 92697-3900, USA.
authors.forename: Dillon
authors.initials: D
authors.lastname: Dejam
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Edinger
authors.affiliation: Departments of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA. Electronic address: agman@chem.northwestern.edu.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA 92697-3900, USA. Electronic address: poulos@uci.edu.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D030562:Databases, Protein; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D007700:Kinetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000201:enzymology*; D051379:Mice; D062105:Molecular Docking Simulation; D016296:Mutagenesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D019001:Nitric Oxide Synthase