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Targeting Bacterial Nitric Oxide Synthase with Aminoquinoline-Based Inhibitors.

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.

SUBMITTER: Holden JK

PROVIDER: S-EPMC5283056 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Targeting Bacterial Nitric Oxide Synthase with Aminoquinoline-Based Inhibitors.

Holden Jeffrey K JK Lewis Matthew C MC Cinelli Maris A MA Abdullatif Ziad Z Pensa Anthony V AV Silverman Richard B RB Poulos Thomas L TL

Biochemistry 20160921 39

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 ...[more]

PMID: 27607918

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Structure-based design of bacterial nitric oxide synthase inhibitors.

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