Intravesically administered human defensin-5 ameliorates E. coli induced catheter associated-urinary tract infections...

The existing treatment approaches against urinary tract infections (UTIs) are associated with severe side effects and antimicrobial resistance. Human defensin-5 (HD-5) is an important component of the innate defense mechanism in the urinary tract. The aim of our study was to evaluate the antimicrobial potential of intravesically administered HD-5 against uropathogenic Escherichia coli (UPEC) in rat cystitis model. To the best of our knowledge, this is the first study to demonstrate the therapeutic role of exogenously administered HD-5, in UTIs. With an MIC of 60 µg/ml against UPEC, HD-5 exerted antimicrobial activity primarily by disrupting membrane integrity, leading to blebbing, release of extracellular contents, and ultimately whole-cell lysis. HD-5 administered via the intravesical route significantly reduced UPEC load by 54% in bladder and 50% in urine. H and E staining of treated bladders indicated reduced inflammation and improved architectural integrity establishing a strong anti-inflammatory potential of HD-5. Also, there was visible improvement in blood parameters like TLC, DLC, Platelets and Haemoglobin in treated animals suggesting its possible immunomodulatory role. The relative efficacy of the tested therapeutic agents was found to be in the order of intravesical HD-5 > oral ciprofloxacin > intravesical ciprofloxacin > oral HD-5 under the present experimental conditions. Interestingly, intravesical dosing of HD-5 was found to be overall effective in the present UTI model, likely due to direct targeting at the site of infection. Our findings establish HD-5 as a potent anti-UPEC agent which can be developed as an alternate strategy to combat hospital-acquired catheter associated UTIs.