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

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d1510b5815fb4a74a8dabbd7ce110eb3
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spelling	oai:doaj.org-article:d1510b5815fb4a74a8dabbd7ce110eb32021-12-02T13:30:09ZA small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections10.1038/s41598-021-83257-22045-2322https://doaj.org/article/d1510b5815fb4a74a8dabbd7ce110eb32021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83257-2https://doaj.org/toc/2045-2322Abstract 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.Scarlet MiloRachel A. HeylenJohn GlancyGeorge T. WilliamsBethany L. PatenallHollie J. HathawayNaing T. ThetSarah L. AllinsonMaisem LaabeiA. Toby A. JenkinsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections
description	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.
format	article
author	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
author_facet	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
author_sort	Scarlet Milo
title	A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections
title_short	A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections
title_full	A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections
title_fullStr	A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections
title_full_unstemmed	A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections
title_sort	small-molecular inhibitor against proteus mirabilis urease to treat catheter-associated urinary tract infections
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d1510b5815fb4a74a8dabbd7ce110eb3
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A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections

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