title: Activity of a novel series of acylides active against community-acquired respiratory pathogens.
abstract: Resistance to macrolides and beta-lactams has increased sharply amongst key respiratory pathogens, leading to major concern. A novel series of acylides was designed to overcome this resistance and was evaluated for in vitro and in vivo activity. This series of acylides was designed starting from clarithromycin by changing the substitution on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. Minimum inhibitory concentrations (MICs) of acylides were determined against susceptible as well as macrolide-lincosamide-streptogramin B (MLS(B))--and penicillin-resistant Streptococcus pneumoniae, Streptococcus pyogenes and Moraxella catarrhalis by the agar dilution method. Microbroth MICs for Haemophilus influenzae were determined according to Clinical and Laboratory Standards Institute guidelines. In vivo efficacy was determined by target organ load reduction against S. pneumoniae 3579 (ermB). The bactericidal potential of promising acylides was also determined. MICs of these compounds against S. pneumoniae, S. pyogenes, H. influenzae and M. catarrhalis were in the range of 0.06-2, 0.125-1, 1-16 and 0.015-0.5 microg/mL, respectively, irrespective of their resistance pattern. Mycoplasma pneumoniae and Legionella pneumophila showed MIC ranges of 0.004-0.125 microg/mL and 0.004-0.03 microg/mL, respectively. The acylides also showed better activity against telithromycin-resistant S. pneumoniae strains. Compounds with a 4-furan-2-yl-1H-imidazolyl side chain on the carbamate (RBx 10000296) showed a target organ load reduction of >3 log(10) colony-forming units/mL and concentration-dependent bactericidal potential against S. pneumoniae 994 mefA and H. influenzae strains. This novel and potent series of acylides active against antibiotic-resistant respiratory pathogens should be further investigated.
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Plot 20, Sector 18, Udyog Vihar, Gurgaon 122 001, Haryana, India. manisha.pandya@ranbaxy.com
authors.forename: Manisha
authors.initials: M
authors.lastname: Pandya
authors.forename: Anjan
authors.initials: A
authors.lastname: Chakrabarti
authors.forename: Sujata
authors.initials: S
authors.lastname: Rathy
authors.forename: Rita
authors.initials: R
authors.lastname: Katoch
authors.forename: R
authors.initials: R
authors.lastname: Venkataraman
authors.forename: Pragya
authors.initials: P
authors.lastname: Bhateja
authors.forename: Tarun
authors.initials: T
authors.lastname: Mathur
authors.forename: G Ram
authors.initials: GR
authors.lastname: Kumar
authors.forename: Sunita
authors.initials: S
authors.lastname: Malhotra
authors.forename: Madhvi
authors.initials: M
authors.lastname: Rao
authors.forename: Tripti
authors.initials: T
authors.lastname: Bhadauria
authors.forename: Tarani Kanta
authors.initials: TK
authors.lastname: Barman
authors.forename: Biswajit
authors.initials: B
authors.lastname: Das
authors.forename: Dilip
authors.initials: D
authors.lastname: Upadhyay
authors.forename: Pradip Kumar
authors.initials: PK
authors.lastname: Bhatnagar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D017291:Clarithromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D017714:Community-Acquired Infections / Q000382:microbiology*; D004353:Drug Evaluation, Preclinical; D006193:Haemophilus influenzae / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D001936:Moraxella catarrhalis / Q000187:drug effects*; D018410:Pneumonia, Bacterial / Q000382:microbiology*; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D017291:Clarithromycin