Author: Lee, Sujin ; Park, Yujin ; Heo, Bo Eun ; Hanh, Bui Thi Bich ; Jang, Jichan ; Kim, Tae Ho ; Nguyen, Thanh Quang ; Moon, Cheol ; Choudhary, Arunima ; Jeon, Seunghyeon ; Min, Sun-Joon

Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. Epetraborole, a benzoxaborole, is a clinical candidate developed for Gram-negative infections and has been confirmed to exhibit favorable activity against a well known pulmonary pathogen, Mycobacterium abscessus. However, according to ClinicalTrials.gov, in 2017, a clinical phase II study on the use of epetraborole to treat complicated urinary tract and intra-abdominal infections was terminated due to the rapid emergence of drug resistance during treatment. Nevertheless, epetraborole is in clinical development for nontuberculous mycobacteria (NTM) disease especially for Mycobacterium avium complex-related pulmonary disease (MAC-PD). DS86760016, an epetraborole analog, was further demonstrated to have an improved pharmacokinetic profile, lower plasma clearance, longer plasma half-life, and higher renal excretion than epetraborole in animal models. In this study, DS86760016 was found to be similarly active against M. abscessus in vitro, intracellularly, and in zebrafish infection models with a low mutation frequency. These results expand the diversity of druggable compounds as new benzoxaborole-based candidates for treating M. abscessus diseases.

01 Apr 2019·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

DS86760016, a Leucyl-tRNA Synthetase Inhibitor with Activity against Pseudomonas aeruginosa

Q2 · MEDICINE

Article

Author: Kashyap, Amuliya ; Kumar, Manoj ; Rao, Madhvi ; Purnapatre, Kedar P. ; Pandya, Manisha ; Bambal, Ramesh B. ; Chaira, Tridib ; Barman, Tarani Kanta ; Masuda, Nobuhisa ; Khodor, Souhaila Al ; Upadhyay, Dilip J. ; Joshi, Vattan

DS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS86760016 showed potent activity against extended-spectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in vitro biofilms.

01 Apr 2018·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

In Vitro and In Vivo Activities of DS86760016, a Novel Leucyl-tRNA Synthetase Inhibitor for Gram-Negative Pathogens

Q2 · MEDICINE

Article

Author: Masuda, Nobuhisa ; Chaira, Tridib ; Rao, Madhvi ; Pandya, Manisha ; Bambal, Ramesh ; Khanna, Alka ; Upadhyay, Dilip J. ; Purnapatre, Kedar P.

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Pseudomonas Infections	Preclinical	India	Daiichi Sankyo India Pharma Pvt Ltd.	27 May 2019

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