Mode of action of Ranbezolid against staphylococci and structural modeling studies of its interaction with ribosomes.
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.
Kalia
Vandana
V
Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
Miglani
Rajni
R
Purnapatre
Kedar P
KP
Mathur
Tarun
T
Singhal
Smita
S
Khan
Seema
S
Voleti
Sreedhara R
SR
Upadhyay
Dilip J
DJ
Saini
Kulvinder Singh
KS
Rattan
Ashok
A
Raj
V Samuel
VS
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
D000081:Acetamides; D000900:Anti-Bacterial Agents; D005663:Furans; D010080:Oxazoles; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; C476340:ranbezolid; D000069349:Linezolid