Infection and blockage of indwelling urinary catheters is significant owing to its high incidence rate and severe medical consequences. Bacterial enzymes are employed as targets for small molecular intervention in human bacterial infections. Urease is a metalloenzyme known to play a crucial role in the pathogenesis and virulence of catheter-associated Proteus mirabilis infection. 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. 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. 2-MA is a structural analogue of urea, showing promising competitive activity against urease. In silico docking experiments demonstrated 2-MA's competitive inhibition, whilst further quantum level modelling suggests two possible binding mechanisms.
Scientific reports. 2021 Feb 12*** epublish ***
Scarlet Milo, Rachel A Heylen, John Glancy, George T Williams, Bethany L Patenall, Hollie J Hathaway, Naing T Thet, Sarah L Allinson, Maisem Laabei, A Toby A Jenkins
Department of Chemistry, University of Bath, Bath, BA2 7AY, UK., School of Physical Sciences, University of Kent, Canterbury, CT2 7NH, UK., Department of Chemistry, Lancaster University, Bailrigg, Lancaster, LA1 4YB, UK., Biomedical and Life Sciences Division, Lancaster University, Bailrigg, Lancaster, LA1 4YB, UK., Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK., Department of Chemistry, University of Bath, Bath, BA2 7AY, UK. .