title: A novel ketolide, RBx 14255, with activity against multidrug-resistant Streptococcus pneumoniae.
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.
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India vethakkani.raj.g6@dsin.co.in.
authors.forename: V Samuel
authors.initials: VS
authors.lastname: Raj
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Tarani Kanta
authors.initials: TK
authors.lastname: Barman
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.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Kedar
authors.initials: K
authors.lastname: Purnapatre
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Smita
authors.initials: S
authors.lastname: Dube
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: G
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Pragya
authors.initials: P
authors.lastname: Bhateja
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Tarun
authors.initials: T
authors.lastname: Mathur
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Tridib
authors.initials: T
authors.lastname: Chaira
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Dilip J
authors.initials: DJ
authors.lastname: Upadhyay
authors.affiliation: Department of Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Yogesh B
authors.initials: YB
authors.lastname: Surase
authors.affiliation: Department of Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: R
authors.initials: R
authors.lastname: Venkataramanan
authors.affiliation: Department of Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Anjan
authors.initials: A
authors.lastname: Chakrabarti
authors.affiliation: Department of Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Das
authors.affiliation: Department of Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Gurgaon, India.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Bhatnagar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D024881:Drug Resistance, Bacterial; D048628:Ketolides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D011500:Protein Synthesis Inhibitors; C580587:Rbx 14255; C106791:telithromycin