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In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation

Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as Staphylococcus aureus. As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considere...

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Autores principales: Thappeta, Kishore Reddy Venkata, Zhao, Li Na, Nge, Choy Eng, Crasta, Sharon, Leong, Chung Yan, Ng, Veronica, Kanagasundaram, Yoganathan, Fan, Hao, Ng, Siew Bee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696255/
https://www.ncbi.nlm.nih.gov/pubmed/33202690
http://dx.doi.org/10.3390/ijms21228601
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author Thappeta, Kishore Reddy Venkata
Zhao, Li Na
Nge, Choy Eng
Crasta, Sharon
Leong, Chung Yan
Ng, Veronica
Kanagasundaram, Yoganathan
Fan, Hao
Ng, Siew Bee
author_facet Thappeta, Kishore Reddy Venkata
Zhao, Li Na
Nge, Choy Eng
Crasta, Sharon
Leong, Chung Yan
Ng, Veronica
Kanagasundaram, Yoganathan
Fan, Hao
Ng, Siew Bee
author_sort Thappeta, Kishore Reddy Venkata
collection PubMed
description Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as Staphylococcus aureus. As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considered a favorable target for the enhancement of novel anti-infective drugs that aim to interfere with key bacterial virulence mechanisms, such as biofilm formation, without developing drug resistance. Here, we used virtual screening to search an in-house natural compound library and identified two natural compounds, N1287 (Skyrin) and N2576 ((4,5-dichloro-1H-pyrrol-2-yl)-[2,4-dihydroxy-3-(4-methyl-pentyl)-phenyl]-methanone) that inhibited the enzymatic activity of SrtA. These compounds also significantly reduced the growth of S. aureus but possessed moderate mammalian toxicity. Furthermore, S. aureus strains treated with these compounds exhibited reduction in adherence to host fibrinogen, as well as biofilm formation. Hence, these compounds may represent an anti-infective therapy without the side effects of antibiotics.
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spelling pubmed-76962552020-11-29 In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation Thappeta, Kishore Reddy Venkata Zhao, Li Na Nge, Choy Eng Crasta, Sharon Leong, Chung Yan Ng, Veronica Kanagasundaram, Yoganathan Fan, Hao Ng, Siew Bee Int J Mol Sci Article Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as Staphylococcus aureus. As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considered a favorable target for the enhancement of novel anti-infective drugs that aim to interfere with key bacterial virulence mechanisms, such as biofilm formation, without developing drug resistance. Here, we used virtual screening to search an in-house natural compound library and identified two natural compounds, N1287 (Skyrin) and N2576 ((4,5-dichloro-1H-pyrrol-2-yl)-[2,4-dihydroxy-3-(4-methyl-pentyl)-phenyl]-methanone) that inhibited the enzymatic activity of SrtA. These compounds also significantly reduced the growth of S. aureus but possessed moderate mammalian toxicity. Furthermore, S. aureus strains treated with these compounds exhibited reduction in adherence to host fibrinogen, as well as biofilm formation. Hence, these compounds may represent an anti-infective therapy without the side effects of antibiotics. MDPI 2020-11-14 /pmc/articles/PMC7696255/ /pubmed/33202690 http://dx.doi.org/10.3390/ijms21228601 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Thappeta, Kishore Reddy Venkata
Zhao, Li Na
Nge, Choy Eng
Crasta, Sharon
Leong, Chung Yan
Ng, Veronica
Kanagasundaram, Yoganathan
Fan, Hao
Ng, Siew Bee
In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation
title In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation
title_full In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation
title_fullStr In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation
title_full_unstemmed In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation
title_short In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation
title_sort in-silico identified new natural sortase a inhibitors disrupt s. aureus biofilm formation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696255/
https://www.ncbi.nlm.nih.gov/pubmed/33202690
http://dx.doi.org/10.3390/ijms21228601
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