Affiliation:
1. Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India
2. Department of Pharmacokinetics and Metabolism, Daiichi Sankyo India Pharma Private Limited, Gurgaon, Haryana, India
Abstract
ABSTRACT
The emergence of multidrug-resistant (MDR) Gram-negative bacilli is a major concern in the treatment of nosocomial infections. Antibacterial agents with novel modes of action can be useful, as these pathogens have become resistant to almost all existing standard-of-care agents. GSK2251052, a leucyl-tRNA synthetase inhibitor, has a novel mode of action against Gram-negative bacteria. However, the phase 2 studies with this drug were terminated due to microbiological failures based on the rapid emergence of drug resistance during the treatment of complicated urinary tract infections. DS86760016 is a novel leucyl-tRNA synthetase inhibitor active against MDR Gram-negative bacteria, such as
Escherichia coli
,
Klebsiella pneumoniae
, and
Pseudomonas aeruginosa
, with an improved pharmacokinetic profile. DS86760016 showed lower plasma clearance, longer plasma half-life, and higher renal excretion than GSK2251052 did in mice, rats, monkeys and dogs. DS86760016 also showed lower mutant prevention concentrations against
P. aeruginosa
than did GSK2251052. No resistant bacteria were observed in murine urinary tract infection models at a dose that maintained urinary concentrations above the mutant prevention concentration. DS86760016 also showed a lower risk of resistance development than did GSK2251052 in comparative
in vivo
studies with murine urinary tract infection models. These results suggest that DS86760016 has potential as a new drug for the treatment of MDR Gram-negative bacterial infections, with a lower risk of drug resistance development than that of GSK2251052.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
18 articles.
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