Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 2, Pages 994-1004Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm501723p
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Funding
- National Institute of Health [GM57353, GM49725]
- NIH [T32 GM108561]
- Xsede grant [TG-MCB130001]
- Department of Energy, Office of Biological and Environmental Research
- National Institutes of Health, National Center for Research Resources, Biomedical Technology Program
- National Institute of General Medical Sciences
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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.
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