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Structural and biological characterization of NOS inhibitors with antimicrobial properties (585.5)
Author(s) -
Holden Jeffrey,
Li Huiying,
Richo Jerry,
Lim Nathan,
Jing Qing,
Kang Soosung,
Huang He,
Silverman Richard,
Poulos Thomas
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.585.5
Subject(s) - antimicrobial , bacillus anthracis , chemistry , nitric oxide synthase , nitric oxide , antibiotics , microbiology and biotechnology , staphylococcus aureus , in vitro , binding site , enzyme , biochemistry , bacteria , biology , genetics , organic chemistry
Nitric oxide produced by bacterial nitric oxide synthase (bNOS) protects Gram‐positive pathogens Bacillus anthracis and Staphylococcus aureus against oxidative stress and a wide variety of antibiotics. Recently, we demonstrated that co‐treatment with NOS inhibitors increases the killing efficacy of a common antimicrobial (1) . Taking an interdisciplinary approach using microbial in vitro assays, spectroscopic binding analyses, enzyme kinetics and X‐ray crystal structures we have identified a series of lead inhibitors for future structure‐based drug design. Crystal structures of lead bNOS inhibitors have revealed an unprecedented mode of binding to the bacterial NOS that has not been previously observed in mammalian homologs. Continued exploitation of this novel‐binding mode will be imperative for rationally designing a potent and selective bNOS inhibitor. Grant Funding Source : National Institute of Health