Currently, acetohydroxamic acid (AHA) is the only licensed urease inhibitor available for antiureolytic therapy (Supplementary Fig. Indeed, the replacement catheter can become rapidly recolonized by bacteria, as it is often placed into the bladder containing a high bacteria titre 5. However, due to struvite and apatite encrustation, removal of blocked catheters is often uncomfortable and painful for the patients. Current treatment of blocked catheters generally consists of antibiotic treatment and a catheter change. Catheter blockage causes incontinence and painful distention of the bladder, and can result in urine reflux to the kidneys, causing pyelonephritis and increasing the risk of sepsis 5, 13. The resultant extensive crystalline biofilm networks are notoriously difficult to treat, are often antibiotic resistant and may remain within the bladder between catheter changes 10, 11, 12. ![]() mirabilis biofilm and attach to the lumen and balloon of the catheter blocking the flow of the urine down to the drainage bag 8, 9. As ammonia is produced, the pH of the urine increases, promoting the formation of struvite (MgNH 4PO 4♶H 2O) and apatite (Ca 10(PO 4CO 3OH) 6(OH) 2) crystals 7. mirabilis is to provide a nitrogen source for the bacteria 4. The primary function of urease expressed by P. Urease (a nickel-dependent metalloenzyme) metabolizes urea to a molecule of carbonic acid and two molecules of ammonia (Supplementary Fig. mirabilis is a Gram-negative, rod-shaped, urease-positive bacteria which forms biofilms on and around the luminal surfaces of the catheter 4. mirabilis) is the most common cause of bacteremia in nursing homes, bearing a high mortality rate owing to the possibility of progression to sepsis 4, 5. CAUTIs accounted for 45,717 excess bed days in the UK National Health Service (NHS) hospitals during 2016–2017 period, and cost the NHS between £1.5 and 2.25 billion per year 2, 3. In silico docking experiments demonstrated 2-MA’s competitive inhibition, whilst further quantum level modelling suggests two possible binding mechanisms.Ĭatheter-associated urinary tract infections (CAUTIs) are the most common hospital acquired infection, affecting approximately 150–250 million patients globally per year 1. 2-MA is a structural analogue of urea, showing promising competitive activity against urease. We describe the design, synthesis, and in vitro evaluation of the small molecular enzyme inhibitor 2-mercaptoacetamide (2-MA), which can prevent encrustation and blockage of urinary catheters in a physiologically representative in vitro model of the catheterized urinary tract. Targeting urease as a therapeutic candidate facilitates the disarming of bacterial virulence without affecting bacterial fitness, thereby limiting the selective pressure placed on the invading population and lowering the rate at which it will acquire resistance. ![]() Urease is a metalloenzyme known to play a crucial role in the pathogenesis and virulence of catheter-associated Proteus mirabilis infection. Bacterial enzymes are employed as targets for small molecular intervention in human bacterial infections. Infection and blockage of indwelling urinary catheters is significant owing to its high incidence rate and severe medical consequences.
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