Nosocomial infections can lead to mortality. They account for approximately 2 million patients per year in the United States. Gram-negative bacteria account for approximately two-thirds of nosocomial infections. Moreover, in intensive care units, Gram-negative bacteria account for ∼70% of infections. However, the extended-spectrum β-lactamase producers and carbapenem-resistant Enterobacteriaceae are forecasted to be the major drug-resistant Gram-negative bacteria in the future. These Gram-negative bacteria develop resistance to existing antibiotics through various mechanisms. They have multiple efflux pumps that can eliminate antibacterial compounds from the cells. They also are highly efficient in upregulating or acquiring genes that code for proteins for antibiotic drug resistance. The aminoacyl-tRNA synthetases are targets for the discovery of new drugs. These enzymes catalyze the activation and attachment of each particular amino acid to its cognate tRNA. In this study, DS86760016 is a potent LeuRS inhibitor. It has activity against multidrug-resistant (MDR) Gram-negative bacteria.

DS86760016 is a novel LeuRS inhibitor active against MDR Gram-negative bacteria.

It inhibits LeuRS enzymes from Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii, with IC50s of 0.38, 0.62, and 0.16 μM, respectively. DS86760016 inhibits some Gram-negative bacteria with MICs ranging from 0.25 to 2 μg/ml. The MIC of DS86760016 against Gram-positive bacteria is >32 μg/ml. Thus, this selective activity of DS86760016 would lead to no risk of resistance development in Gram-positive bacteria. In addition, DS86760016 shows a 2- to 4-log reduction in bacterial loads in the kidney at the 7.5- and 15-mg/kg doses, respectively, when tested against susceptible and MDR clinical isolates of E. coli, K. pneumoniae, and P. aeruginosa. Ciprofloxacin shows efficacy similar to that of DS86760016 when tested against the susceptible strains, but it did not show efficacy against the MDR strains. In addition, it shows moderate spontaneous resistance (FSR).

In summary, DS86760016 is a potent LeuRS inhibitor. It 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.


Purnapatre KP, et al. Antimicrob Agents Chemother. 2018;62(4):e01987-17. Published 2018 Mar 27.