In Vitro Activity of TR-700, the Antibacterial Moiety of the Prodrug TR-701, against Linezolid-Resistant Strains

Abstract

TR-701 is the orally active prodrug of TR-700, a novel oxazolidinone that demonstrates four-to eightfoldgreater activity than linezolid (LZD) against Staphylococcus and Enterococcus spp. In this study evaluating the in vitro sensitivity of LZD-resistant isolates, TR-700 demonstrated 8-to 16-fold-greater potency than LZD against all strains tested, including methicillin-resistant Staphylococcus aureus (MRSA), strains of MRSA carrying the mobile cfr methyltransferase gene, and vancomycin-resistant enterococci. The MIC 90 for TR-700 against LZD-resistant S. aureus was 2 g/ml, demonstrating the utility of TR-700 against LZD-resistant strains. A model of TR-700 binding to 23S rRNA suggests that the increased potency of TR-700 is due to additional target site interactions and that TR-700 binding is less reliant on target residues associated with resistance to LZD.Oxazolidinone antibiotics are one of the newest classes of antibiotics developed within the past 30 years, with linezolid (LZD) representing the only marketed member of this class. In 2000, LZD (Zyvox) was granted approval for the treatment of infections associated with vancomycin-resistant Enterococcus faecium, nosocomial pneumonia, community-acquired pneumonia due to Streptococcus pneumoniae and methicillin-sensitive Staphylococcus aureus (MSSA), and complicated skin and skin structure infections, including cases due to methicillinresistant Staphylococcus aureus (MRSA) (1). Later approvals included pediatric use, pneumonia due to multidrugresistant S. pneumoniae, and treatment of diabetic foot infections, without osteomyelitis, caused by gram-positive bacteria. These approvals represent important milestones for the novel oxazolidinone class in the treatment of serious infections.Oxazolidinones have been shown to bind to the 50S ribosomal subunit and inhibit protein translation (31). A model of the binding of LZD to the 23S rRNA peptidyl transferase region has been previously published, based upon in vivo crosslinking experiments (18). This model predicts that LZD would specifically interfere with the binding of the amino acid portion of the aminoacyl tRNA to the ribosomal A site. The recent crystal structure of LZD bound to the 50S ribosomal subunit confirms these findings and suggests that the mechanism of inhibition involves competition with the incoming A site substrates (13). Mutations in the 23S rRNA central loop of domain V, the peptidyl transferase center (PTC), are associated with the development of LZD resistance.

Targeting Antibiotic Resistance

“…Escherichia coli numbering in parentheses. Model was generated with Chimera 1.10.1 according to K. J. Shaw et al 14, 35…”

New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides

“…Tedizolid inhibits the synthesis of bacterial proteins by interacting with the 23S rRNA component of the 50S ribosomal subunit (5). The drug has activity against staphylococci, streptococci, and enterococci, including some strains that have lost susceptibility to vancomycin, daptomycin, and linezolid (Table 1) (6)(7)(8). Additionally, tedizolid has activity against linezolid-resistant Staphylococcus aureus with the cfr multidrug resistance gene mutation (6).…”

“…The drug has activity against staphylococci, streptococci, and enterococci, including some strains that have lost susceptibility to vancomycin, daptomycin, and linezolid (Table 1) (6)(7)(8). Additionally, tedizolid has activity against linezolid-resistant Staphylococcus aureus with the cfr multidrug resistance gene mutation (6). Compared to linezolid, tedizolid has been shown to have 4-to 16-fold greater in vitro activity against methicillin-susceptible Staphylococcus aureus (MSSA), MRSA, streptococci, and enterococci (9).…”

New Antibiotics in the Therapy of Osteomyelitis

“…The molecule inhibits translation by binding to the bacterial 23S ribosome initiation complex [100] . Its spectrum covers Grampositive pathogens, including linezolid-resistant S. aureus [101] .…”