In-Vivo Efficacy Of A Novel Leu-T-Rna Synthatase Inhibitor Compound A Against Mdr Pseudomonas Aeruginosa 1594965 In A Foreign Body Associated Urinary Tract Infection Model

Background: Pseudomonas aeruginosa is one of the major pathogens causing morbidity and mortality in hospital acquired infections (HAI). MDR P. aeruginosa are resistant to 3 or more classes of antibiotics. In cUTI cases catheter associated infections are incurable by most of the antibiotics. Compound A a novel Leu-t-RNA synthetase inhibitor showed efficacy in mouse ascending urinary tract infection (AUTI) model against P. aeruginosa biofilms formed on urinary catheters. Methods & Materials: In this study we established a mouse model of foreign body associated AUTI. A spiral polyethylene tube (PT) was placed transurethrally into bladder without surgical manipulation, followed by transurethral inoculation with Pseudomonas aeruginosa 1594965 (MDR) strain. Scanning electron microscopy (SEM) was done after 4h of inoculation of bacteria and bacterial counts were taken in kidneys, bladders and catheter pieces for respective samples. In vivo efficacy of Compound A was tested using this established model against P. aeruginosa 1594965(Compound A MIC: 1 μg/ml, meropenem MIC: 32 μg/ml). Compound A was tested at 30 and 220mg/kg SC q6h and meropenem was tested at human simulated dose of 60 mg/kg SC q6h. The treatment was initiated 4h post infection and continued daily for 7 days. Bacterial counts of placebo 4h, 7 days and 7 days treated group's samples of kidneys, bladders and catheters were calculated. Data was analysed using bacterial counts of each group and compared with those of 4 h placebo control group. Results: SEM showed good establishment of biofilm in 4 h samples. In foreign body associated mouse infection model. LRS inhibitor Compound A at 30, 220 mg/kg SC q6h showed log10 difference of -2.38, -2.18 log10 CFU/kidney respectively compared to 4h placebo and meropenem at 60 mg/kg SC q6h was inefficacious. In bladders this log difference was -2.30, -1.21, -0.78 respectively. On catheter only Compound A at 220mg/kg SC q6h showed log10 difference of -1.59 log10CFU/ml. No efficacy was observed in remaining groups Conclusion: Efficacy of Compound A in foreign body associated mouse AUTI infection model against MDR Pseudomonas aeruginosa 1594965 proves its efficacy on biofilm. These results warrant its further investigation in HAI associated Pseudomonas aeruginosa infections.