5,5′ -methylenedisalicylic acid (MDSA) modulates SarA/MgrA phosphorylation by targeting Ser/Thr phosphatase stp1

Weihao Zheng; Yujie Liang; Hui Zhao; Jianing Zhang; Zigang Li

doi:10.1002/cbic.201500003

5,5′ -methylenedisalicylic acid (MDSA) modulates SarA/MgrA phosphorylation by targeting Ser/Thr phosphatase stp1

Weihao Zheng, Yujie Liang, Hui Zhao, Jianing Zhang, Zigang Li^*

^*Corresponding author for this work

Peking University

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

Abstract

SarA (staphylococcal accessory protein A), MgrA (MarR family of global transcriptional regulator A), and SarZ (a paralogue of SarA) play critical roles in modulating the virulence, drug resistance and autolysis of Staphylococcus aureus. Recently, eukaryotic-like Ser/Thr kinase/phosphatases (Stk1/Stp1) were found to modulate phosphorylation of these transcriptional regulators as well as staphylococcal virulence. Importantly, an stp1-deficient strain showed significant virulence reduction in mice, indicative of Stp1 as a potential drug target. Here, we report that MDSA, an inhibitor of MgrA, enhances phosphorylation of SarA/MgrA by inhibiting Stp1 in S. aureus. MDSA is a more-potent inhibitor (IC₅₀=9.68±0.52 μM) of Stp1 than commonly used phosphatase inhibitors. We anticipate that MDSA could be a lead compound to develop new approaches for reducing staph virulence by targeting Stp1.

Original language	English
Pages (from-to)	1035-1040
Number of pages	6
Journal	ChemBioChem
Volume	16
Issue number	7
DOIs	https://doi.org/10.1002/cbic.201500003
Publication status	Published - 4 May 2015
Externally published	Yes

Keywords

global regulators
inhibitors
Staphylococcus aureus
Stp1
structure-activity relationships

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10.1002/cbic.201500003

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title = "5,5′ -methylenedisalicylic acid (MDSA) modulates SarA/MgrA phosphorylation by targeting Ser/Thr phosphatase stp1",

abstract = "SarA (staphylococcal accessory protein A), MgrA (MarR family of global transcriptional regulator A), and SarZ (a paralogue of SarA) play critical roles in modulating the virulence, drug resistance and autolysis of Staphylococcus aureus. Recently, eukaryotic-like Ser/Thr kinase/phosphatases (Stk1/Stp1) were found to modulate phosphorylation of these transcriptional regulators as well as staphylococcal virulence. Importantly, an stp1-deficient strain showed significant virulence reduction in mice, indicative of Stp1 as a potential drug target. Here, we report that MDSA, an inhibitor of MgrA, enhances phosphorylation of SarA/MgrA by inhibiting Stp1 in S. aureus. MDSA is a more-potent inhibitor (IC50=9.68±0.52 μM) of Stp1 than commonly used phosphatase inhibitors. We anticipate that MDSA could be a lead compound to develop new approaches for reducing staph virulence by targeting Stp1.",

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author = "Weihao Zheng and Yujie Liang and Hui Zhao and Jianing Zhang and Zigang Li",

note = "Publisher Copyright: {\textcopyright} 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",

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AU - Zheng, Weihao

AU - Liang, Yujie

AU - Zhao, Hui

AU - Zhang, Jianing

AU - Li, Zigang

PY - 2015/5/4

Y1 - 2015/5/4

N2 - SarA (staphylococcal accessory protein A), MgrA (MarR family of global transcriptional regulator A), and SarZ (a paralogue of SarA) play critical roles in modulating the virulence, drug resistance and autolysis of Staphylococcus aureus. Recently, eukaryotic-like Ser/Thr kinase/phosphatases (Stk1/Stp1) were found to modulate phosphorylation of these transcriptional regulators as well as staphylococcal virulence. Importantly, an stp1-deficient strain showed significant virulence reduction in mice, indicative of Stp1 as a potential drug target. Here, we report that MDSA, an inhibitor of MgrA, enhances phosphorylation of SarA/MgrA by inhibiting Stp1 in S. aureus. MDSA is a more-potent inhibitor (IC50=9.68±0.52 μM) of Stp1 than commonly used phosphatase inhibitors. We anticipate that MDSA could be a lead compound to develop new approaches for reducing staph virulence by targeting Stp1.

AB - SarA (staphylococcal accessory protein A), MgrA (MarR family of global transcriptional regulator A), and SarZ (a paralogue of SarA) play critical roles in modulating the virulence, drug resistance and autolysis of Staphylococcus aureus. Recently, eukaryotic-like Ser/Thr kinase/phosphatases (Stk1/Stp1) were found to modulate phosphorylation of these transcriptional regulators as well as staphylococcal virulence. Importantly, an stp1-deficient strain showed significant virulence reduction in mice, indicative of Stp1 as a potential drug target. Here, we report that MDSA, an inhibitor of MgrA, enhances phosphorylation of SarA/MgrA by inhibiting Stp1 in S. aureus. MDSA is a more-potent inhibitor (IC50=9.68±0.52 μM) of Stp1 than commonly used phosphatase inhibitors. We anticipate that MDSA could be a lead compound to develop new approaches for reducing staph virulence by targeting Stp1.

KW - global regulators

KW - inhibitors

KW - Staphylococcus aureus

KW - Stp1

KW - structure-activity relationships

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JF - ChemBioChem

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ER -

5,5′ -methylenedisalicylic acid (MDSA) modulates SarA/MgrA phosphorylation by targeting Ser/Thr phosphatase stp1

Abstract

Keywords

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