1. A novel ketolide, RBx 14255, with activity against multidrug-resistant Streptococcus pneumoniae.
- Author
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Raj VS, Barman TK, Kalia V, Purnapatre K, Dube S, G R, Bhateja P, Mathur T, Chaira T, Upadhyay DJ, Surase YB, Venkataramanan R, Chakrabarti A, Das B, and Bhatnagar PK
- Subjects
- Animals, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents pharmacokinetics, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Resistance, Bacterial, Ketolides chemical synthesis, Ketolides pharmacokinetics, Male, Mice, Microbial Sensitivity Tests, Pneumonia, Bacterial microbiology, Pneumonia, Bacterial mortality, Pneumonia, Bacterial pathology, Protein Synthesis Inhibitors chemical synthesis, Protein Synthesis Inhibitors pharmacokinetics, Ribosomes drug effects, Ribosomes metabolism, Sepsis microbiology, Sepsis mortality, Sepsis pathology, Streptococcus pneumoniae pathogenicity, Streptococcus pneumoniae physiology, Survival Analysis, Anti-Bacterial Agents pharmacology, Ketolides pharmacology, Pneumonia, Bacterial drug therapy, Protein Synthesis Inhibitors pharmacology, Sepsis drug therapy, Streptococcus pneumoniae drug effects
- Abstract
We present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for its in vitro and in vivo activities against sensitive and macrolide-resistant Streptococcus pneumoniae. RBx 14255 showed excellent in vitro activity against macrolide-resistant S. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae 3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistant S. pneumoniae 3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. The in vivo efficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation of S. pneumoniae ATCC 6303 and systemic infection with S. pneumoniae 3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 against S. pneumoniae ATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistant S. pneumoniae 3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
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