u-100480 and tedizolid

The natural resistance of rapidly growing mycobacteria (RGM) to multiple antibiotics renders the treatment of the infections caused less successful. The objective of this study was to evaluate the in vitro susceptibilities of four oxazolidinones against different RGM species.. The microplate alamarBlue assay was performed to identify the minimum inhibitory concentrations (MICs) of four oxazolidinones - delpazolid, sutezolid, tedizolid, and linezolid - for 32 reference strains and 115 clinical strains of different RGM species. The MIC breakpoint concentration was defined as 16 μg/ml for linezolid. Next, the gene fragments associated with oxazolidinone resistance were amplified and sequenced, and mutations were defined in contrast with the sequences of the reference strains.. Tedizolid showed the strongest inhibitory activity against the Mycobacterium abscessus isolates. Delpazolid exhibited better antimicrobial activity against the Mycobacterium fortuitum isolates when compared to linezolid, with 4-fold lower MIC values. The protein alignment and structure-based analysis showed that there might be no correlation between oxazolidinone resistance and mutations in the rplC, rplD, and 23S rRNA genes in the tested RGM.. Tedizolid had the strongest inhibitory activity against M. abscessus in vitro, while delpazolid presented the best inhibitory activity against M. fortuitum. This provides important insights into the potential clinical application of oxazolidinones to treat RGM infections.

Topics: Anti-Bacterial Agents; Beijing; Humans; Linezolid; Microbial Sensitivity Tests; Mycobacterium abscessus; Oxazolidinones; Tetrazoles

Non-human primates (NHP) are thought to be a good preclinical animal model for tuberculosis because they develop disease characteristics that are similar to humans. The objective of the current study was to determine if NHPs can also be used to reliably predict the exposure of tedizolid, sutezolid, and its biologically active metabolite sutezolid-M1 in humans. The prodrug tedizolid phosphate and sutezolid were administered orally to NHPs either once or twice daily for up to eight days. The active moieties, tedizolid, and sutezolid showed linear pharmacokinetics and respective concentration-time profiles could be described by one-compartment body models with first-order elimination. One additional metabolite compartment with first-order elimination was found appropriate to capture the pharmacokinetics of sutezolid-M1. Once allometrically scaled to humans with a fixed exponent of 0.75 for apparent clearance and 1 for apparent volume of distribution, the AUCs of tedizolid and sutezolid were predicted reasonably well, whereas C

Topics: Animals; Anti-Bacterial Agents; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Oxazolidinones; Primates; Tetrazoles

Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Disease Models, Animal; Female; Linezolid; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Oxazolidinones; Rifampin; Tetrazoles

A method for the enantioseparation of sutezolid, the next analogue after linezolid and tedizolid, belonging to the truly new class of antibacterial agents, the oxazolidinones, was developed based on non-aqueous capillary electrophoresis (NACE), using a single isomer of cyclodextrins as a chiral pseudophase. During the experiment, the enantioseparation of sutezolid together with its predecessor, linezolid, both weak base antibacterial agents, was evaluated using anionic single-isomers of cyclodextrins from hydrophilic, up to hydrophobic: heptakis-(2,3-dihydroxy-6-sulfo)-β-cyclodextrin, heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD), as well as heptakis-(2,3-dimethyl-6-sulfo)-β-cyclodextrin (HDMS-β-CD), respectively. Based on the observed results, the cyclodextrins, HDAS-β-CD and HDMS-β-CD which carry the acetyl and methyl groups at the C2 and C3 positions, respectively, provided the baseline separation of sutezolid enantiomers. However, HDMS-β-CD led to a reversal of enantiomer migration order (EMO) in comparison to HDAS-β-CD. Instead, enantiomers of linezolid were separated only by HDMS-β-CD. During the experiments, different organic solvents and their mixtures in various ratios were tested. The selectivity and separation efficiency were critically affected by the nature of the buffer system, the type of organic solvent, and the concentrations of trifluoroacetic acid (TFA) in the NACE buffer system. Focusing on the desired EMO in which the eutomers (S)-sutezolid and (S)-linezolid migrated last, the highest enantioresolution using the NACE method was achieved at normal polarity mode with 45  mM HDMS-β-CD dissolved in MeOH/ACN (85:15, v/v) containing 200  mM TFA/20  mM ammonium formate. Moreover, infrared spectroscopy, NMR and molecular modelling were investigated to provide information about complex formation.

Topics: beta-Cyclodextrins; Cyclodextrins; Electrophoresis, Capillary; Linezolid; Magnetic Resonance Spectroscopy; Models, Molecular; Oxazolidinones; Spectrophotometry, Infrared; Stereoisomerism; Tetrazoles