title: Structure-based design of bacterial nitric oxide synthase inhibitors.
abstract: Inhibition of bacterial nitric oxide synthase (bNOS) has the potential to improve the efficacy of antimicrobials used to treat infections by Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis. However, inhibitor specificity toward bNOS over the mammalian NOS (mNOS) isoforms remains a challenge because of the near identical NOS active sites. One key structural difference between the NOS isoforms is the amino acid composition of the pterin cofactor binding site that is adjacent to the NOS active site. Previously, we demonstrated that a NOS inhibitor targeting both the active and pterin sites was potent and functioned as an antimicrobial ( Holden , , Proc. Natl. Acad. Sci. U.S.A. 2013 , 110 , 18127 ). Here we present additional crystal structures, binding analyses, and bacterial killing studies of inhibitors that target both the active and pterin sites of a bNOS and function as antimicrobials. Together, these data provide a framework for continued development of bNOS inhibitors, as each molecule represents an excellent chemical scaffold for the design of isoform selective bNOS inhibitors.
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences and Chemistry, University of California , 2206 Nat. Sci. 1, Irvine, California 92697-3900, United States.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Holden
authors.forename: Soosung
authors.initials: S
authors.lastname: Kang
authors.forename: Scott A
authors.initials: SA
authors.lastname: Hollingsworth
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.forename: Nathan
authors.initials: N
authors.lastname: Lim
authors.forename: Steven
authors.initials: S
authors.lastname: Chen
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D013876:Thiophenes; D019001:Nitric Oxide Synthase