Nitric Oxide Synthase Inhibitors (NOS-I)
Author: Larry H Bernstein, MD, FCAP
Curator: Stephen J. Williams, PhD
and
Co-Curator: Aviva Lev-Ari, PhD, RN
This recent article sheds a new light on nitric oxide and the activity of NOS in reactive oxygen species generation and the effect of NOS inhibitors in bacteria.
Structural and Biological Studies on Bacterial Nitric Oxide Synthase Inhibitors
Jeffrey K. Holdena, Huiying Lia, Qing Jingb, Soosung Kangb, Jerry Richoa, Richard B. Silvermanb,1, and Thomas L. Poulosb,1
Agman@chem.northwestern.edu
Author contributions: J.K.H. designed research; J.K.H. and J.R. performed research; Q.J. and S.K. contributed new reagents/analytic tools; J.K.H., H.L., R.B.S., and T.L.P. analyzed data; and J.K.H., R.B.S., and T.L.P. wrote the paper.
PNAS Oct 21, 2013; http://dx.doi.org/10.1073/pnas.1314080110
This article is a PNAS Direct Submission
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank
Edited by Douglas C. Rees, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, and approved September 23, 2013 (received for review July 29, 2013)
Keywords: crystallography, antibiotics, nitric oxide, NOS inhibitors, Bacillus subtilis, gram positive bacteria
Significance
Nitric oxide (NO) produced by bacterial nitric oxide synthase has recently been shown to
- protect the Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus from
- antibiotics and oxidative stress.
Using Bacillus subtilis as a model system, we identified
- two NOS inhibitors that work in conjunction with an antibiotic to kill B. subtilis.
Moreover, comparison of inhibitor-bound crystal structures between the bacterial NOS and mammalian NOS revealed an unprecedented
- mode of binding to the bacterial NOS that can be further exploited for future structure-based drug design.
Overall, this work is an important advance in developing inhibitors against gram-positive pathogens.
Abstract
Nitric oxide (NO) produced by bacterial NOS functions as
- a cytoprotective agent against oxidative stress in Staphylococcus aureus, Bacillus anthracis, and Bacillus subtilis.
The screening of several NOS-selective inhibitors uncovered two inhibitors with potential antimicrobial properties. These two compounds
- impede the growth of B. subtilis under oxidative stress, and
- crystal structures show that each compound exhibits a unique binding mode.
Both compounds serve as excellent leads for the future development of antimicrobials against bacterial NOS-containing bacteria.
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This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.