802. Oxazolidinones
Session: Symposium: New Molecules from Old Classes: Is There Still Room for Improvement?
Saturday, October 25, 2008: 12:00 AM
Room: Room 150B
The oxazolidinones, exemplified by linezolid (marketed as Zyvox®), are a relatively new class of totally synthetic antibacterial agents that demonstrate clinically useful levels of activity against problematic Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA), multidrug-resistant Streptococcus pneumoniae (MDRSP) and vancomycin-resistant enterococci (VRE). At the time of its approval by the FDA in 2000, linezolid was the first example of a novel class to be entered into clinical use in over 35 years. The oxazolidinones employ a unique mechanism of action involving inhibition of bacterial protein synthesis, selectively binding to the 50S ribosomal subunit. Resistance mutations, cross-linking studies and ultimately an X-ray co-crystal structure have mapped oxazolidinone binding to domain V of the ribosome 23S rRNA. Specifically, the oxazolidinones bind to the A-site of the peptidyl transferase center and interfere with subsequent binding of aminoacyl-t-RNA. The lack of cross-resistance with other antibacterial agent classes, combined with available oral and intravenous dosage forms, amongst other characteristics, has led to broad acceptance of linezolid into clinical practice. Nevertheless, linezolid remains the only marketed oxazolidinone some 8 years after its introduction. The reasons for this situation will be discussed. Selected new pre-clinical and clinical oxazolidinones in the post-linezolid approval period will also be presented, with an emphasis on compounds that offer possible advantages over their progenitor. Desirable properties such as increased activity, expanded spectrum, enhanced pharmacokinetics, potential coverage of linezolid-resistant organisms, and possible improvements in safety will be the focus of the discussion.
Michael Barbachyn, PhD, AstraZeneca Pharm., LP, Waltham, MA and  M. R. Barbachyn, None.

Biographical Sketch for Michael R. Barbachyn:
Michael R. Barbachyn did his undergraduate work at Calvin College in Grand Rapids, Michigan and then went on to receive his Ph.D. in Organic Chemistry from Wayne State University in 1983, working under the direction of Professor Carl R. Johnson. After a NIH Postdoctoral Fellow stint with Professor Samuel Danishefsky at Yale University, he joined The Upjohn Company in 1985. During his tenure with Upjohn, Pharmacia & Upjohn, Pharmacia, Pfizer, and now AstraZeneca, Mike has been intimately involved with research in the anti-infective area. As a highlight, from 1991-2002 Mike was directly involved with the oxazolidinone antibacterial agent discovery effort, serving as the project team co-leader for several years in the mid to late 1990’s. As part of this overall effort, he had the good fortune of co-inventing linezolid, marketed as Zyvox®, the first clinically useful oxazolidinone antibacterial agent. In recognition of this, Mike has received an Upjohn Award (2001), ACS Regional Industrial Innovation Award (2003), ACS National Award for Team Innovation (2007), and the PhRMA Discoverers Award (2007). Mike is an inventor on 37 US Patents and has authored or co-authored 40 papers & chapters in the chemistry and anti-infective fields. Mike is currently serving as a Director in the Infection Discovery area at AstraZeneca in Boston, Massachusetts.