title: In Vitro and In Vivo Activities of a Bi-Aryl Oxazolidinone, RBx 11760, against Gram-Positive Bacteria.
abstract: RBx 11760, a bi-aryl oxazolidinone, was investigated for antibacterial activity against Gram-positive bacteria. The MIC90s of RBx 11760 and linezolid against Staphylococcus aureus were 2 and 4 mg/liter, against Staphylococcus epidermidis were 0.5 and 2 mg/liter, and against Enterococcus were 1 and 4 mg/liter, respectively. Similarly, against Streptococcus pneumoniae the MIC90s of RBx 11760 and linezolid were 0.5 and 2 mg/liter, respectively. In time-kill studies, RBx 11760, tedizolid, and linezolid exhibited bacteriostatic effect against all tested strains except S. pneumoniae RBx 11760 showed 2-log10kill at 4× MIC while tedizolid and linezolid showed 2-log10and 1.4-log10kill at 16× MIC, respectively, against methicillin-resistant S. aureus (MRSA) H-29. Against S. pneumoniae 5051, RBx 11760 showed bactericidal activity, with 4.6-log10kill at 4× MIC compared to 2.42-log10and 1.95-log10kill for tedizolid and linezolid, respectively, at 16× MIC. RBx 11760 showed postantibiotic effects (PAE) at 3 h at 4 mg/liter against MRSA H-29, and linezolid showed the same effect at 16 mg/liter. RBx 11760 inhibited biofilm production against methicillin-resistant S. epidermidis (MRSE) ATCC 35984 in a concentration-dependent manner. In a foreign-body model, linezolid and rifampin resulted in no advantage over stasis, while the same dose of RBx 11760 demonstrated a significant killing compared to the initial control against S. aureus (P < 0.05) and MRSE (P < 0.01). The difference in killing was statistically significant for the lower dose of RBx 11760 (P < 0.05) versus the higher dose of linezolid (P > 0.05 [not significant]) in a groin abscess model. In neutropenic mouse thigh infection, RBx 11760 showed stasis at 20 mg/kg of body weight, whereas tedizolid showed the same effect at 40 mg/kg. These data support RBx 11760 as a promising investigational candidate.
authors.affiliation: Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.|Centre for Biomedical Engineering, Indian Institute of Technology, New Delhi, India.
authors.forename: Tarani Kanta
authors.initials: TK
authors.lastname: Barman
authors.affiliation: Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.
authors.forename: Tarun
authors.initials: T
authors.lastname: Mathur
authors.affiliation: Department of Pharmacokinetics & Metabolism, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.
authors.forename: Tridib
authors.initials: T
authors.lastname: Chaira
authors.affiliation: Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.
authors.forename: G
authors.initials: G
authors.lastname: Ramkumar
authors.affiliation: Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.|Department of Scientific and Industrial Research, Government of India, New Delhi, India.
authors.forename: Vandana
authors.initials: V
authors.lastname: Kalia
authors.affiliation: Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.
authors.forename: Madhvi
authors.initials: M
authors.lastname: Rao
authors.affiliation: Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Pandya
authors.affiliation: Department of Medicinal Chemistry, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.
authors.forename: Ajay Singh
authors.initials: AS
authors.lastname: Yadav
authors.affiliation: Department of Medicinal Chemistry, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Das
authors.affiliation: Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India.
authors.forename: Dilip J
authors.initials: DJ
authors.lastname: Upadhyay
authors.affiliation: Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh, India.
authors.lastname: Hamidullah
authors.affiliation: Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh, India.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.affiliation: Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India samuelrajv@yahoo.com harpal2000@yahoo.com.|Centre for Drug Design Discovery and Development (C4D), SRM University Haryana, Sonepat, Haryana, India.
authors.forename: V Samuel
authors.initials: VS
authors.lastname: Raj
authors.affiliation: Centre for Biomedical Engineering, Indian Institute of Technology, New Delhi, India samuelrajv@yahoo.com harpal2000@yahoo.com.
authors.forename: Harpal
authors.initials: H
authors.lastname: Singh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018441:Biofilms; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D000069349:Linezolid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000188:drug therapy / Q000382:microbiology; D010755:Organophosphates / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D023303:Oxazolidinones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011704:Pyelonephritis / Q000188:drug therapy / Q000382:microbiology; D017208:Rats, Wistar; D017192:Skin Diseases, Bacterial / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; D023303:Oxazolidinones; C000622535:RBx 11760; D000069349:Linezolid; C515040:tedizolid phosphate