Targeting Bacterial Nitric Oxide Synthase with Aminoquinoline-Based Inhibitors

Jeffrey K. Holden, Matthew C. Lewis, Maris A. Cinelli, Ziad Abdullatif, Anthony V. Pensa, Richard B. Silverman*, Thomas L. Poulos

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Nitric oxide is produced in Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus by the bacterial isoform of nitric oxide synthase (NOS). Inhibition of bacterial nitric oxide synthase (bNOS) has been identified as a promising antibacterial strategy for targeting methicillin-resistant S. aureus [Holden, J. K., et al. (2015) Chem. Biol. 22, 785-779]. One class of NOS inhibitors that demonstrates antimicrobial efficacy utilizes an aminoquinoline scaffold. Here we report on a variety of aminoquinolines that target the bacterial NOS active site, in part, by binding to a hydrophobic patch that is unique to bNOS. Through mutagenesis and crystallographic studies, our findings demonstrate that aminoquinolines are an excellent scaffold for further aiding in the development of bNOS specific inhibitors.

Original languageEnglish (US)
Pages (from-to)5587-5594
Number of pages8
JournalBiochemistry
Volume55
Issue number39
DOIs
StatePublished - Oct 4 2016

ASJC Scopus subject areas

  • Biochemistry

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