A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections

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

Research output: Contribution to journalArticlepeer-review

15 Citations (SciVal)

Abstract

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.

Original languageEnglish
Article number3726
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - 12 Feb 2021

Bibliographical note

Funding Information:
Scarlet Milo and Rachel Heylen would like to thank the Annette Trust for their funding. Rachel Heylen and John Glancy (Centre for Sustainable and Circular Technologies) would like to thank the EPSRC Doctoral Training Account and George Williams would like to thank the University of Kent GCDC for their funding. Bethany Patenall would like to thank the James Tudor Foundation and Mr and Mrs A. Watson for their funding.

ASJC Scopus subject areas

  • General

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