Biological Activity
DS86760016 is a potent leucyl-tRNA synthetase (LeuRS) inhibitor with activity against multidrug-resistant (MDR) Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. DS86760016 inhibits LeuRS enzymes from Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii, with IC50s of 0.38, 0.62, and 0.16 μM, respectively[1][2].
DS86760016 inhibits some Gram-negative bacteria with an MICs ranging from 0.25 to 2 μg/ml. The MIC of DS86760016 against Gram-positive bacteria is >32 μg/ml. DS86760016 is active against both susceptible and these MDR P. aeruginosa, E. coli, and K. pneumoniae strains, with an MIC90 of 2 μg/ml[1].
DS86760016 (7.5-220 mg/kg; s.c.; q6h for 7 days) shows moderate spontaneous resistance (FSR)[1].The pharmacokinetic (PK) parameters of DS86760016 in mouse, rat, monkey, and dog plasma by the intravenous (i.v.) route are test. DS86760016 shows lower intravenous plasma clearances (CLp) of 11, 29, 5.6, and 4.5 ml/min/kg in mouse, rat, monkey, and dog plasma, respectively. The plasma half-lives (t1/2) for DS86760016 are 1.9, 1.5, 8.6, and 8.3 h in mice, rats, monkeys, and dogs, respectively. The lower plasma clearance resulted in higher plasma exposures for DS86760016, with dose-normalized areas under the curve after i.v. administration (DNAUCIVs) of 1.5, 0.6, 3.7, and 3.0 μg h kg/ml/mg in mice, rats, monkeys, and dogs, respectively[1].
References
[1]. Purnapatre KP, et al. In Vitro and In Vivo Activities of DS86760016, a Novel Leucyl-tRNA Synthetase Inhibitor for Gram-Negative Pathogens. Antimicrob Agents Chemother. 2018;62(4):e01987-17. Published 2018 Mar 27.[2]. Kumar M, et al. DS86760016, a Leucyl-tRNA Synthetase Inhibitor with Activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2019;63(4):e02122-18. Published 2019 Mar 27.
