ABSTRACT
OBJECTIVES AND METHODS: DRF 8417, a novel oxazolidinone, has been evaluated against Gram-positive and fastidious Gram-negative bacteria. In vitro activity of DRF 8417 was determined by broth microdilution method and in vivo efficacy studies were carried out in different murine systemic infection models. RESULTS: DRF 8417 exhibited potent activity against Gram-positive pathogens with MIC(50) and MIC(90) values ranging from 0.06 to 1 mg/L. MICs against Haemophilus influenzae and Moraxella catarrhalis were one to two dilutions lower than those of linezolid. The in vivo efficacy, by oral route, in different susceptible and resistant Gram-positive systemic bacterial infection models ranged from 2.0 to 2.9 mg/kg. CONCLUSIONS: These studies displayed the excellent in vitro and in vivo activity of DRF 8417 against Gram-positive pathogens and lower MICs when compared with linezolid against H. influenzae and M. catarrhalis.
Subject(s)
Anti-Infective Agents , Gram-Negative Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Cocci/drug effects , Haemophilus influenzae/drug effects , Moraxella catarrhalis/drug effects , Oxazolidinones , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Disease Models, Animal , Female , Gram-Negative Bacterial Infections/microbiology , Gram-Positive Bacterial Infections/microbiology , Haemophilus Infections/drug therapy , Haemophilus Infections/microbiology , Haemophilus influenzae/enzymology , Humans , Male , Mice , Microbial Sensitivity Tests , Moraxellaceae Infections/drug therapy , Moraxellaceae Infections/microbiology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Specific Pathogen-Free Organisms , Treatment Outcome , beta-Lactam Resistance , beta-Lactamases/metabolismABSTRACT
The solid-phase synthesis of branched lacto-N-neohexaose derivative 1 occurring in human milk is described. The new building block of lactose 3 bearing the orthogonal temporary hydroxy protecting groups 9-fluorenylmethyloxycarbonyl (Fmoc) and levulinoyl (Lev) has been prepared. Its use, together with that of lactosamine donor 4, glucosamine donor 5, and O-galactosyl trichloroacetimidate 6, has enabled the preparation of hexasaccharide 22 following two different approaches in excellent overall yield (43%, 90% per step over eight steps). An additional key feature of this work is the successful use of newly prepared ester-type linker 2, having a benzylic spacer connected to the anomeric oxygen. This linker presents the advantage of producing a benzylic anomeric moiety after cleavage from the polymer support, which could be easily removed to obtain the unprotected oligosaccharide 1.