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

Scarlet Milo,Bethany L Patenall,George T Williams,Naing T Thet,Maisem Laabei,Hollie J Hathaway,John Glancy,Rachel A Heylen,A Toby A Jenkins,Sarah L Allinson

doi:10.1038/s41598-021-83257-2

Scarlet Milo, Bethany L Patenall + Show 8 more

Open Access

https://doi.org/10.1038/s41598-021-83257-2

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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.

Highlights

Infection and blockage of indwelling urinary catheters is significant owing to its high incidence rate and severe medical consequences
This study aimed to identify an inhibitor of the urease enzyme, which is produced by the uropathogenic bacteria P. mirabilis
Drugs that function as enzyme inhibitors constitute a significant portion of the orally bioavailable therapeutic agents that are in clinical use today

Summary

Introduction

Infection and blockage of indwelling urinary catheters is significant owing to its high incidence rate and severe medical consequences. 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. Previously described the development and analysis of a library of N-alpha mercaptoamide dipeptide inhibitors against Zap A protease (a virulence factor known to play a key role in P. mirabilis pathogenesis)[22]. Despite their in vitro success in inhibiting ZapA, these inhibitors showed negligible activity against urease (unpublished data, not shown). Quantum mechanical (QM) computational modelling hypothesizes two possible 2-MA’s binding mechanisms and allows comparison to the licensed drug AHA

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