In Vitro and In Vivo Activities of DS86760016, a Novel Leucyl-tRNA Synthetase Inhibitor for Gram-Negative Pathogens
| Autor: | Ramesh B. Bambal, Tridib Chaira, Kedar Purnapatre, Dilip J. Upadhyay, Madhvi Rao, Manisha Pandya, Alka Khanna, Nobuhisa Masuda |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pharmacology Gram-negative bacteria biology Pseudomonas aeruginosa Klebsiella pneumoniae 030106 microbiology Drug resistance biology.organism_classification medicine.disease_cause Microbiology Multiple drug resistance 03 medical and health sciences Infectious Diseases In vivo medicine Pharmacology (medical) Experimental Therapeutics Mode of action Bacteria |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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