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Antimicrobial Agents and Chemotherapy, March 2002, p. 625-629, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.625-629.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

1H Nuclear Magnetic Resonance Study of Oxazolidinone Binding to Bacterial Ribosomes

Casey Chun Zhou,{dagger} Steven M. Swaney, Dean L. Shinabarger, and Brian J. Stockman*

Pharmacia Corporation, Kalamazoo, Michigan 49001

Received 7 June 2001/ Returned for modification 11 November 2001/ Accepted 10 December 2001

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 µM and 195 ± 40 µM 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 PNU-177553 and eperezolid but not in their inactive enantiomers.

* Corresponding author. Mailing address: Pharmacia Corporation, Structural, Analytical & Medicinal Chemistry, 301 Henrietta St., Kalamazoo, MI 49001. Phone: (616) 833-1882. Fax: (616) 833-1822. E-mail: brian.j.stockman{at}pharmacia.com.

{dagger} Present address: Abbott Laboratories, Dept. 418, NC R13/141, North Chicago, IL 60064.

Antimicrobial Agents and Chemotherapy, March 2002, p. 625-629, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.625-629.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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