linezolid and tedizolid

A series of novel substituted pyridyl phenyl oxazolidinone analogues were synthesized and their structure-activity relationship (SAR) was investigated based on in vitro and in vivo antibacterial activities. The minimum inhibitory concentrations (MICs) of the synthesized compounds against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) ranged from 0.12 to 2.0 μg/mL, and against Haemophilus influenzae (Hi) from 2.0 to 8.0 μg/mL. Compared to linezolid, only four compounds (11, 12, 21 and 29) showed higher in vitro antibacterial activities and better in vivo protective effects in mice. To improve the aqueous solubility, various prodrugs of compound 11 (DA-7157), which exerted a potency that was enhanced by 2-8-fold compared to that of linezolid, were synthesized. Among the prodrugs, the phosphate compound 42 exhibited excellent aqueous solubility (>50mg/mL in DW) and good pharmacokinetic profiles, along with better in vivo efficacy than linezolid. This compound 42 is currently undergoing clinical trials with the brand name Torezolid.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Discovery; Male; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Oxazolidinones; Prodrugs; Solubility; Tetrazoles

The in vitro activity of TR-700 (torezolid) was evaluated against a collection of 660 staphylococcal blood isolates. TR-700 showed excellent activity against all the staphylococci tested. The MIC(50) and MIC(90) values of TR-700, linezolid, daptomycin, and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) isolates were 0.25 and 0.5, 2 and 4, 0.5 and 0.5, and 1 and 2 microg/ml, respectively. TR-700 demonstrated greater in vitro potency than linezolid against staphylococci, including linezolid-resistant and vancomycin-nonsusceptible strains, and was 32-fold more active than linezolid against the seven cfr-positive MRSA strains tested.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; In Vitro Techniques; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Sepsis; Spain; Staphylococcal Infections; Tetrazoles; Vancomycin

This study assessed the spectrum of activity of torezolid (TR-700), the active moiety of torezolid phosphate (TR-701), and proposes tentative MIC and disk diffusion breakpoints as well as quality control ranges. The in vitro susceptibilities of 1,096 bacterial isolates, representing 23 different species or phenotypic groups, were determined for torezolid, linezolid, cefotaxime, and levofloxacin using Clinical and Laboratory Standards Institute (CLSI) broth microdilution MICs, minimum bactericidal concentrations (MBCs), agar dilution, and disk diffusion testing methods. Torezolid was very active against the majority of Gram-positive strains, including methicillin-susceptible and -resistant Staphylococcus aureus (MIC(50) = 0.25 microg/ml, MIC(90)

Topics: Disk Diffusion Antimicrobial Tests; Drug Resistance, Bacterial; Enterococcaceae; Gram-Positive Bacteria; History, Medieval; In Vitro Techniques; Indicator Dilution Techniques; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbiological Techniques; Organophosphates; Oxazoles; Oxazolidinones; Quality Control; Streptococcus; Tetrazoles

Following recent reports of ribosomal protein L3 mutations in laboratory-derived linezolid-resistant (LZD(r)) Staphylococcus aureus, we investigated whether similar mutations were present in LZD(r) staphylococci of clinical origin. Sequence analysis of a variety of LZD(r) isolates revealed two L3 mutations, DeltaSer145 (S. aureus NRS127) and Ala157Arg (Staphylococcus epidermidis 1653059), both occurring proximal to the oxazolidinone binding site in the peptidyl transferase center. The oxazolidinone torezolid maintained a >or=8-fold potency advantage over linezolid for both strains.

Topics: Acetamides; Binding Sites; Drug Resistance, Bacterial; Linezolid; Mutation; Oxazolidinones; Protein Structure, Secondary; Ribosomal Protein L3; Ribosomal Proteins; RNA, Ribosomal, 23S; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Tetrazoles