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The article discusses the issue of catheter blockage caused by urease-positive organisms in urinary catheters, which can lead to urinary tract infections. It mentions that the current urease inhibitor, acetohydroxamic acid (AHA), has side effects and is rarely used. The researchers used a rational in silico drug design approach to discover new urease inhibitors, identified three compounds, and tested them in in vitro assays. One of the compounds, N,N′-Bis(3-pyridinylmethyl)thiourea (Bis-TU), outperformed AHA and significantly extended the lifetime of the catheter in in vitro bladder model testing. The study demonstrates a cost-effective drug design approach for developing potent urease inhibitors that could be further improved and applied to target other diseases.
Catheter associated urinary tract infections (CAUTI) caused by urease-positive organisms can lead to catheter blockage: urease metabolizes urea in urine to ammonia causing an increase in pH and hence precipitation of struvite and apatite salts into the catheter lumen and bladder leading to blockage. Acetohydroxamic acid (AHA) is the only urease inhibitor currently approved for patient use, however, it is rarely used owing to its side effects. Here, we report the identification and development of new urease inhibitors discovered using a rational in silico drug design approach. A series of compounds were designed, the compounds were screened and filtered to identify three compounds which were tested in in vitro urease activity assays. N,N′-Bis(3-pyridinylmethyl)thiourea (Bis-TU) outperformed AHA in activity assays and was tested in an in vitro bladder model, where it significantly extended the lifetime of the catheter compared to AHA. Bis-TU was delivered via a diffusible balloon catheter directly to the site of activity, thus demonstrating localized drug delivery. This cost-effective drug design approach allowed the identification of a potent urease inhibitor, which could be improved through iterative repeats of the method, and the process of design could be utilized to target other diseases.
This article is Open Access
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