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Author Swaney, Steven M. ♦ Shinabarger, Dean L. ♦ Stockman, Brian J.
Source CiteSeerX
Content type Text
File Format PDF
Language English
Subject Domain (in DDC) Computer science, information & general works ♦ Data processing & computer science
Subject Keyword Oxazolidinone Binding ♦ Trnoe Experiment ♦ Nuclear Magnetic Resonance ♦ Different Conformation ♦ Dissociation Constant ♦ Novel Class ♦ Ring C5 Side Chain ♦ Novel Mechanism ♦ Line-broadening Analysis ♦ Several Oxazolidinones ♦ Positive No ♦ Extended Conformation ♦ Small Molecule ♦ Proper Orientation ♦ Negative No ♦ Protein Synthesis ♦ Specific Binding ♦ Antibacterial Activity ♦ 4-fold Decrease ♦ Corresponding Enantiomer ♦ Nuclear Overhauser Enhancement ♦ Bacterial Ribosome ♦ Nuclear Magnetic Resonance Study ♦ Observed No ♦ Nmr-derived Dissociation Constant ♦ Similar Affinity
Description The oxazolidinones are a novel class of antibiotics that inhibit initiation of protein synthesis in bacteria. In order to investigate their novel mechanism of action, the interactions of several oxazolidinones with bacterial 70S ribosomes, 50S subunits, and 30S subunits have been characterized by 1H nuclear magnetic resonance (NMR) line-broadening analyses and transferred nuclear Overhauser enhancement (TRNOE) experiments. PNU-177553 and PNU-100592 (eperezolid) and their corresponding enantiomers, PNU-184414 and PNU-107112, were studied. The dissociation constants were determined to be 94 44 M and 195 40 M for PNU-177553 and eperezolid, respectively. There was a 4-fold decrease in affinity for their corresponding enantiomers. The NMR-derived dissociation constants are consistent with their antibacterial activity. PNU-177553 and eperezolid were found to bind only to the 50S subunit, with similar affinity as to the 70S ribosome, and to have no affinity for the 30S subunit. Specific binding of PNU-177553 was further confirmed in TRNOE experiments in which positive NOEs observed for the small molecule alone were changed to negative NOEs in the presence of bacterial 70S ribosomes. The observed NOEs indicated that PNU-177553 did not adopt a significantly different conformation when bound to the 70S ribosome, compared to the extended conformation that exists when free in solution. Since this is likeliest the case for each of the four compounds included in this study, the A ring C5 side chain may be positioned in the proper orientation for antibacterial activity in
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Age Range above 22 year
Educational Use Research
Education Level UG and PG ♦ Career/Technical Study
Learning Resource Type Article
Publisher Institution MODE OF ACTION OF RANBEZOLID 1433 o n February 27, 2014 by PENN STATE UNIV http://aac.asm .org/ D ow nloaded from