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

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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

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© 2014 American Chemical Society.


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