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

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 ,, and , 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 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 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.

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

“…DS86760016 showed a superior activity with an MIC 50/90 of 1/2 g/ml compared to the standard antipseudomonas agents, meropenem, ciprofloxacin, and tobramycin (MIC 90 Ͼ 32 g/ml) ( Table 1). DS86760016 showed a narrow MIC range and Ͼ8-fold lower mutant prevention concentrations (MPC) against P. aeruginosa than GSK2251052 (15). Reduced MPC for DS86760016 might be the result of a differential interaction of the compound with the Pseudomonas LeuRS enzyme, as suggested by a difference in mutation sites in GSK2251052-and DS86760016-resistant mutants (15).…”

“…Benzoxaboroles are a novel class of antibiotics that exhibit excellent activity against Gram-negative pathogens by inhibiting the editing site of the leucyl-tRNAsynthetase (LeuRS) enzyme (14)(15)(16)(17). GSK2251052 was the first benzoxaborole compound with potent activity against drug-resistant Gram-negative organisms (16,17); however, its development was halted during phase II clinical trials because of the rapid selection of resistant mutants (18).…”

“…DS86760016 is a new investigational benzoxaborole compound (see Fig. S1 in the supplemental material) which showed a potent activity against Gram-negative pathogens, excellent pharmacokinetics (PK), and a reduced risk of resistance in mouse ascending UTI models compared to GSK2251052 (15). In this study, we evaluated the activity of DS86760016 against MDR P. aeruginosa with the prospect of its potential use in treating Pseudomonas infections.…”

“…Blood and urine were collected at different time intervals up to 24 h and 72 h postinjection, respectively. Plasma samples were harvested, and PK parameters were calculated as described previously (15). The human intravenous urine profile was simulated according to the allometry of mouse, rat, monkey, and dog PK parameters and human renal and plasma clearance (15).…”

“…Plasma samples were harvested, and PK parameters were calculated as described previously (15). The human intravenous urine profile was simulated according to the allometry of mouse, rat, monkey, and dog PK parameters and human renal and plasma clearance (15). The graphs show that at an intravenous dose of 220 mg/kg/dose q.i.d.…”