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Mechanisms of Action: Physiological Effects

Rχ-01, a New Family of Oxazolidinones That Overcome Ribosome-Based Linezolid Resistance

Eugene Skripkin, Timothy S. McConnell, Joseph DeVito, Laura Lawrence, Joseph A. Ippolito, Erin M. Duffy, Joyce Sutcliffe, François Franceschi
Eugene Skripkin
Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, Connecticut 06511
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Timothy S. McConnell
Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, Connecticut 06511
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Joseph DeVito
Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, Connecticut 06511
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Laura Lawrence
Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, Connecticut 06511
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Joseph A. Ippolito
Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, Connecticut 06511
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Erin M. Duffy
Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, Connecticut 06511
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Joyce Sutcliffe
Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, Connecticut 06511
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François Franceschi
Rib-X Pharmaceuticals, Inc., 300 George Street, Suite 301, New Haven, Connecticut 06511
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  • For correspondence: ffranceschi@rib-x.com
DOI: 10.1128/AAC.01193-07
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ABSTRACT

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, Rχ-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 Rχ-01 family displace, more effectively than linezolid, compounds known to bind to the ribosomal A site. We also monitored binding by assessing whether Rχ-01 compounds protect U2585 (Escherichia coli numbering), a nucleotide that influences peptide bond formation and peptide release, from chemical modification by carbodiimide. The Rχ-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 Rχ-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 Rχ-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 Rχ-01 family of compounds is currently undergoing clinical trials.

  • Copyright © 2008 American Society for Microbiology
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Rχ-01, a New Family of Oxazolidinones That Overcome Ribosome-Based Linezolid Resistance
Eugene Skripkin, Timothy S. McConnell, Joseph DeVito, Laura Lawrence, Joseph A. Ippolito, Erin M. Duffy, Joyce Sutcliffe, François Franceschi
Antimicrobial Agents and Chemotherapy Sep 2008, 52 (10) 3550-3557; DOI: 10.1128/AAC.01193-07

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Rχ-01, a New Family of Oxazolidinones That Overcome Ribosome-Based Linezolid Resistance
Eugene Skripkin, Timothy S. McConnell, Joseph DeVito, Laura Lawrence, Joseph A. Ippolito, Erin M. Duffy, Joyce Sutcliffe, François Franceschi
Antimicrobial Agents and Chemotherapy Sep 2008, 52 (10) 3550-3557; DOI: 10.1128/AAC.01193-07
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KEYWORDS

Acetamides
Anti-Bacterial Agents
oxazolidinones
ribosomes
Staphylococcus aureus

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