In Vitro and In Vivo Activities of a Bi-Aryl Oxazolidinone, RBx 11760, against Gram-Positive Bacteria

Author:

Barman Tarani Kanta12,Kumar Manoj1,Mathur Tarun1,Chaira Tridib3,Ramkumar G.1,Kalia Vandana14,Rao Madhvi1,Pandya Manisha1,Yadav Ajay Singh5,Das Biswajit5,Upadhyay Dilip J.1,Hamidullah 6,Konwar Rituraj6,Raj V. Samuel17,Singh Harpal2

Affiliation:

1. Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India

2. Centre for Biomedical Engineering, Indian Institute of Technology, New Delhi, India

3. Department of Pharmacokinetics & Metabolism, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India

4. Department of Scientific and Industrial Research, Government of India, New Delhi, India

5. Department of Medicinal Chemistry, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India

6. Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh, India

7. Centre for Drug Design Discovery and Development (C4D), SRM University Haryana, Sonepat, Haryana, India

Abstract

ABSTRACT RBx 11760, a bi-aryl oxazolidinone, was investigated for antibacterial activity against Gram-positive bacteria. The MIC 90 s 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 MIC 90 s 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-log 10 kill at 4× MIC while tedizolid and linezolid showed 2-log 10 and 1.4-log 10 kill at 16× MIC, respectively, against methicillin-resistant S. aureus (MRSA) H-29. Against S. pneumoniae 5051, RBx 11760 showed bactericidal activity, with 4.6-log 10 kill at 4× MIC compared to 2.42-log 10 and 1.95-log 10 kill 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.

Funder

Daiichi Sankyo India Pharma Private Limited

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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