Structure-based design of bacterial nitric oxide synthase inhibitors

Jeffrey K. Holden, Soosung Kang, Scott A. Hollingsworth, Huiying Li, Nathan Lim, Steven Chen, He Huang, Fengtian Xue, Wei Tang, Richard B. Silverman*, Thomas L. Poulos

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)994-1004
Number of pages11
JournalJournal of Medicinal Chemistry
Volume58
Issue number2
DOIs
StatePublished - Jan 22 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Holden, J. K., Kang, S., Hollingsworth, S. A., Li, H., Lim, N., Chen, S., Huang, H., Xue, F., Tang, W., Silverman, R. B., & Poulos, T. L. (2015). Structure-based design of bacterial nitric oxide synthase inhibitors. Journal of Medicinal Chemistry, 58(2), 994-1004. https://doi.org/10.1021/jm501723p