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Title: Structure-based design of bacterial nitric oxide synthase inhibitors

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. 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. Lastly, 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.

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [2];  [2];  [2];  [2];  [1]
  1. Univ. of California, Irvine, CA (United States)
  2. Northwestern Univ., Evanston, IL (United States)
Publication Date:
Research Org.:
Univ. of California, Irvine, CA (United States); Northwestern Univ., Evanston, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States)
OSTI Identifier:
1347698
Grant/Contract Number:  
GM49725; GM57353; T32 GM108561
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 58; Journal Issue: 2; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Holden, Jeffrey K., Kang, Soosung, Hollingsworth, Scott A., Li, Huiying, Lim, Nathan, Chen, Steven, Huang, He, Xue, Fengtian, Tang, Wei, Silverman, Richard B., and Poulos, Thomas L. Structure-based design of bacterial nitric oxide synthase inhibitors. United States: N. p., 2014. Web. doi:10.1021/jm501723p.
Holden, Jeffrey K., Kang, Soosung, Hollingsworth, Scott A., Li, Huiying, Lim, Nathan, Chen, Steven, Huang, He, Xue, Fengtian, Tang, Wei, Silverman, Richard B., & Poulos, Thomas L. Structure-based design of bacterial nitric oxide synthase inhibitors. United States. doi:10.1021/jm501723p.
Holden, Jeffrey K., Kang, Soosung, Hollingsworth, Scott A., Li, Huiying, Lim, Nathan, Chen, Steven, Huang, He, Xue, Fengtian, Tang, Wei, Silverman, Richard B., and Poulos, Thomas L. Thu . "Structure-based design of bacterial nitric oxide synthase inhibitors". United States. doi:10.1021/jm501723p. https://www.osti.gov/servlets/purl/1347698.
@article{osti_1347698,
title = {Structure-based design of bacterial nitric oxide synthase inhibitors},
author = {Holden, Jeffrey K. and Kang, Soosung and Hollingsworth, Scott A. and Li, Huiying and Lim, Nathan and Chen, Steven and Huang, He and Xue, Fengtian and Tang, Wei and Silverman, Richard B. and Poulos, Thomas L.},
abstractNote = {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. 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. Lastly, 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.},
doi = {10.1021/jm501723p},
journal = {Journal of Medicinal Chemistry},
number = 2,
volume = 58,
place = {United States},
year = {2014},
month = {12}
}

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Cited by: 7 works
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Works referencing / citing this record:

Cu-Catalyzed switchable synthesis of functionalized pyridines and pyrroles
journal, January 2018

  • Ling, Zheng; Xie, Fang; Gridnev, Ilya D.
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