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

Abstract

DS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS86760016 showed potent activity against extendedspectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in vitro biofilms. In a murine catheter-associated urinary tract infection model, DS86760016 treatment resulted in significant eradication of P. aeruginosa from the kidney, bladder, and catheter without developing drug resistance. Our data suggest that DS86760016 has the potential to act as a new drug for the treatment of Pseudomonas infections.

Azithromycin Exhibits Activity Against Pseudomonas aeruginosa in Chronic Rat Lung Infection Model

“…To further determine the effect of azithromycin against planktonic cells and biofilm formation on a solid surface, we performed a time-kill kinetic study using a catheter piece as a solid surface objective, as described earlier (Kumar et al, 2019), although azithromycin showed a substantial 1.86 log 10 reduction in planktonic cell counts at 6 h as compared to the drug-free control and but no effect at 24 h post-incubation (Figure 2A and Supplementary Figure 3). Possibly, overexpression of multidrug efflux pumps could be the reason of its poor activity against P. aeruginosa in LB media, as potent-activity of azithromycin has been observed in the presence of known efflux pump inhibitors or eukaryotic media (RPMI 1640) (Buyck et al, 2012).…”

“…The effect of azithromycin and clindamycin on P. aeruginosa biofilm formation was assessed as described previously (Sharma et al, 2009;Barman et al, 2016;Kumar et al, 2019). Briefly, the overnight-grown culture of P. aeruginosa PAO1 in TSB was pelleted and resuspended in Luria-Bertani broth containing 0.2% glucose (10 7 CFU/ml).…”

“…The tubes were incubated at 26 ± 2 • C. The planktonic cell counts were determined at various time-points by serial dilution plating onto a trypticase soy agar plate. After 24 h of incubation, the catheter pieces from each tube were removed, non-adherent bacteria were washed from the catheter pieces, and the number of CFU embedded in biofilm per catheter was determined as described earlier (Kumar et al, 2016(Kumar et al, , 2019. The experiment was performed in triplicate, and the mean log 10 killing of planktonic cells and biofilm inhibition were calculated for each concentration.…”

“…The antibiotics of choice for Gram-negative pathogens are parenteral carbapenems, such asimipenem and meropenemor quinolones (Bassetti et al, 2018). However, the poor activities of these antibiotics on bacterial biofilms and the increasing prevalence of multidrug-resistant P. aeruginosa (Cabot et al, 2012;Ciofu and Tolker-Nielsen, 2019;Kumar et al, 2019) leave the physicians with very limited choices to effectively treat these patients.…”

Clinical Efficacy and In Vitro Drug Sensitivity Test Results of Azithromycin Combined With Other Antimicrobial Therapies in the Treatment of MDR P. aeruginosa Ventilator-Associated Pneumonia

“…The treatment options for nosocomial Gram-negative infections are very limited. The poor activities of these antibiotics on bacterial biofilms and the increasing prevalence of MDR P. aeruginosa leave the physicians with very limited choices to effectively treat these patients ( Bassetti et al, 2018 ; Ciofu and Tolker Nielsen, 2019 ; Kumar et al, 2019 ). Antibiotic-resistant biofilms exist widely in P. aeruginosa infection, which is one of the important reasons for the failure of antibacterial treatment.…”