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Antimicrobial Agents and Chemotherapy, October 2008, p. 3550-3557, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.01193-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

R{chi}-01, a New Family of Oxazolidinones That Overcome Ribosome-Based Linezolid Resistance{triangledown}

Eugene Skripkin,{dagger} Timothy S. McConnell,{dagger} Joseph DeVito,{dagger} Laura Lawrence, Joseph A. Ippolito, Erin M. Duffy, Joyce Sutcliffe, and François Franceschi*

Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, Connecticut 06511

Received 10 September 2007/ Returned for modification 19 December 2007/ Accepted 5 July 2008

New and improved antibiotics are urgently needed to combat the ever-increasing number of multidrug-resistant bacteria. In this study, we characterized several members of a new oxazolidinone family, R{chi}-01. This antibiotic family is distinguished by having in vitro and in vivo activity against hospital-acquired, as well as community-acquired, pathogens. We compared the 50S ribosome binding affinity of this family to that of the only marketed oxazolidinone antibiotic, linezolid, using chloramphenicol and puromycin competition binding assays. The competition assays demonstrated that several members of the R{chi}-01 family displace, more effectively than linezolid, compounds known to bind to the ribosomal A site. We also monitored binding by assessing whether R{chi}-01 compounds protect U2585 (Escherichia coli numbering), a nucleotide that influences peptide bond formation and peptide release, from chemical modification by carbodiimide. The R{chi}-01 oxazolidinones were able to inhibit translation of ribosomes isolated from linezolid-resistant Staphylococcus aureus at submicromolar concentrations. This improved binding corresponds to greater antibacterial activity against linezolid-resistant enterococci. Consistent with their ribosomal A-site targeting and greater potency, the R{chi}-01 compounds promote nonsense suppression and frameshifting to a greater extent than linezolid. Importantly, the gain in potency does not impact prokaryotic specificity as, like linezolid, the members of the R{chi}-01 family show translation 50% inhibitory concentrations that are at least 100-fold higher for eukaryotic than for prokaryotic ribosomes. This new family of oxazolidinones distinguishes itself from linezolid by having greater intrinsic activity against linezolid-resistant isolates and may therefore offer clinicians an alternative to overcome linezolid resistance. A member of the R{chi}-01 family of compounds is currently undergoing clinical trials.

* Corresponding author. Mailing address: Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, CT 06511. Phone: (203) 848-6272. Fax: (203) 624-5627. E-mail: ffranceschi{at}rib-x.com

{triangledown} Published ahead of print on 28 July 2008.

{dagger} E.S., T.S.M., and J.D. contributed equally to this work.

Antimicrobial Agents and Chemotherapy, October 2008, p. 3550-3557, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.01193-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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