title: Mode of action of Ranbezolid against staphylococci and structural modeling studies of its interaction with ribosomes.
abstract: Oxazolidinones are known to inhibit protein biosynthesis and act against a wide spectrum of gram-positive bacteria. A new investigational oxazolidinone, ranbezolid, inhibited bacterial protein synthesis in Staphylococcus aureus and Staphylococcus epidermidis. In S. epidermidis, ranbezolid showed inhibition of cell wall and lipid synthesis and a dose-dependent effect on membrane integrity. A kill-kinetics study showed that ranbezolid was bactericidal against S. epidermidis. In vitro translation of the luciferase gene done using bacterial and mammalian ribosomes indicated that ranbezolid specifically inhibited the bacterial ribosome. Molecular modeling studies revealed that both linezolid and ranbezolid fit in similar manners the active site of ribosomes, with total scores, i.e., theoretical binding affinities after consensus, of 5.2 and 6.9, respectively. The nitrofuran ring in ranbezolid is extended toward C2507, G2583, and U2584, and the nitro group forms a hydrogen bond from the base of G2583. The interaction of ranbezolid with the bacterial ribosomes clearly helps to elucidate its potent activity against the target pathogen.
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Vandana
authors.initials: V
authors.lastname: Kalia
authors.forename: Rajni
authors.initials: R
authors.lastname: Miglani
authors.forename: Kedar P
authors.initials: KP
authors.lastname: Purnapatre
authors.forename: Tarun
authors.initials: T
authors.lastname: Mathur
authors.forename: Smita
authors.initials: S
authors.lastname: Singhal
authors.forename: Seema
authors.initials: S
authors.lastname: Khan
authors.forename: Sreedhara R
authors.initials: SR
authors.lastname: Voleti
authors.forename: Dilip J
authors.initials: DJ
authors.lastname: Upadhyay
authors.forename: Kulvinder Singh
authors.initials: KS
authors.lastname: Saini
authors.forename: Ashok
authors.initials: A
authors.lastname: Rattan
authors.forename: V Samuel
authors.initials: VS
authors.lastname: Raj
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D005663:Furans / Q000494:pharmacology*; D000069349:Linezolid; D010080:Oxazoles / Q000494:pharmacology*; D023303:Oxazolidinones / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012270:Ribosomes / Q000187:drug effects* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects*; D013212:Staphylococcus epidermidis / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D005663:Furans; D010080:Oxazoles; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; C476340:ranbezolid; D000069349:Linezolid