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Identification of novel inhibitors of Escherichia coli DNA ligase

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Identification of novel inhibitors of Escherichia coli DNA ligase. / Alomari, Arqam Mohamad Azhar Msbah; Gowland, Robert Michael Nicholas; Southwood, Callum; Barrow, Jak; Bentley, Zoe; Calvin-Nelson, Jashel; Kaminski, Alice; LeFevre, Matthew; Callaghan, Anastasia; Vincent, Helen; Gowers, Darren.

In: Molecules, Vol. 26, No. 9, 2508, 25.04.2021.

Research output: Contribution to journalArticlepeer-review

Harvard

Alomari, AMAM, Gowland, RMN, Southwood, C, Barrow, J, Bentley, Z, Calvin-Nelson, J, Kaminski, A, LeFevre, M, Callaghan, A, Vincent, H & Gowers, D 2021, 'Identification of novel inhibitors of Escherichia coli DNA ligase', Molecules, vol. 26, no. 9, 2508. https://doi.org/10.3390/molecules26092508

APA

Alomari, A. M. A. M., Gowland, R. M. N., Southwood, C., Barrow, J., Bentley, Z., Calvin-Nelson, J., Kaminski, A., LeFevre, M., Callaghan, A., Vincent, H., & Gowers, D. (2021). Identification of novel inhibitors of Escherichia coli DNA ligase. Molecules, 26(9), [2508]. https://doi.org/10.3390/molecules26092508

Vancouver

Alomari AMAM, Gowland RMN, Southwood C, Barrow J, Bentley Z, Calvin-Nelson J et al. Identification of novel inhibitors of Escherichia coli DNA ligase. Molecules. 2021 Apr 25;26(9). 2508. https://doi.org/10.3390/molecules26092508

Author

Alomari, Arqam Mohamad Azhar Msbah ; Gowland, Robert Michael Nicholas ; Southwood, Callum ; Barrow, Jak ; Bentley, Zoe ; Calvin-Nelson, Jashel ; Kaminski, Alice ; LeFevre, Matthew ; Callaghan, Anastasia ; Vincent, Helen ; Gowers, Darren. / Identification of novel inhibitors of Escherichia coli DNA ligase. In: Molecules. 2021 ; Vol. 26, No. 9.

Bibtex

@article{a49266c1565443b98eb855c2546ee01d,
title = "Identification of novel inhibitors of Escherichia coli DNA ligase",
abstract = "Present in all organisms, DNA ligases catalyse the formation of a phosphodiester bond between a 3´ hydroxyl and a 5´ phosphate, a reaction that is essential for maintaining genome integrity during replication and repair. Eubacterial DNA ligases use NAD+ as a cofactor and possess low sequence and structural homology relative to eukaryotic DNA ligases which use ATP as a cofactor. These key differences enable specific targeting of bacterial DNA ligases as an antibacterial strategy. In this study, four small molecule accessible sites within functionally important regions of Escherichia coli ligase (EC-LigA) were identified using in silico methods. Molecular docking was then used to screen for small molecules predicted to bind to these sites. Eight candidate inhibitors were then screened for inhibitory activity in an in vitro ligase assay. Five of these (geneticin, chlorhexidine, glutathione (reduced), imidazolidinyl urea and 2-(aminomethyl)imidazole) showed dose-dependent inhibition of EC-LigA with half maximal inhibitory concentrations (IC50) in the micromolar to millimolar range (11-2600 μM). Two (geneticin and chlorhexidine) were predicted to bind to a region of EC-LigA that has not been directly investigated previously, raising the possibility that there may be amino acids within this region that are important for EC-LigA activity or that the function of essential residues proximal to this region are impacted by inhibitor interactions with this region. We anticipate that the identified small molecule binding sites and inhibitors could be pursued as part of an antibacterial strategy targeting bacterial DNA ligases.",
keywords = "RCUK, BBSRC, BB/J016179/1",
author = "Alomari, {Arqam Mohamad Azhar Msbah} and Gowland, {Robert Michael Nicholas} and Callum Southwood and Jak Barrow and Zoe Bentley and Jashel Calvin-Nelson and Alice Kaminski and Matthew LeFevre and Anastasia Callaghan and Helen Vincent and Darren Gowers",
year = "2021",
month = apr,
day = "25",
doi = "10.3390/molecules26092508",
language = "English",
volume = "26",
journal = "Molecules",
issn = "1420-3049",
publisher = "Multidisciplinary Digital Publishing Institute",
number = "9",

}

RIS

TY - JOUR

T1 - Identification of novel inhibitors of Escherichia coli DNA ligase

AU - Alomari, Arqam Mohamad Azhar Msbah

AU - Gowland, Robert Michael Nicholas

AU - Southwood, Callum

AU - Barrow, Jak

AU - Bentley, Zoe

AU - Calvin-Nelson, Jashel

AU - Kaminski, Alice

AU - LeFevre, Matthew

AU - Callaghan, Anastasia

AU - Vincent, Helen

AU - Gowers, Darren

PY - 2021/4/25

Y1 - 2021/4/25

N2 - Present in all organisms, DNA ligases catalyse the formation of a phosphodiester bond between a 3´ hydroxyl and a 5´ phosphate, a reaction that is essential for maintaining genome integrity during replication and repair. Eubacterial DNA ligases use NAD+ as a cofactor and possess low sequence and structural homology relative to eukaryotic DNA ligases which use ATP as a cofactor. These key differences enable specific targeting of bacterial DNA ligases as an antibacterial strategy. In this study, four small molecule accessible sites within functionally important regions of Escherichia coli ligase (EC-LigA) were identified using in silico methods. Molecular docking was then used to screen for small molecules predicted to bind to these sites. Eight candidate inhibitors were then screened for inhibitory activity in an in vitro ligase assay. Five of these (geneticin, chlorhexidine, glutathione (reduced), imidazolidinyl urea and 2-(aminomethyl)imidazole) showed dose-dependent inhibition of EC-LigA with half maximal inhibitory concentrations (IC50) in the micromolar to millimolar range (11-2600 μM). Two (geneticin and chlorhexidine) were predicted to bind to a region of EC-LigA that has not been directly investigated previously, raising the possibility that there may be amino acids within this region that are important for EC-LigA activity or that the function of essential residues proximal to this region are impacted by inhibitor interactions with this region. We anticipate that the identified small molecule binding sites and inhibitors could be pursued as part of an antibacterial strategy targeting bacterial DNA ligases.

AB - Present in all organisms, DNA ligases catalyse the formation of a phosphodiester bond between a 3´ hydroxyl and a 5´ phosphate, a reaction that is essential for maintaining genome integrity during replication and repair. Eubacterial DNA ligases use NAD+ as a cofactor and possess low sequence and structural homology relative to eukaryotic DNA ligases which use ATP as a cofactor. These key differences enable specific targeting of bacterial DNA ligases as an antibacterial strategy. In this study, four small molecule accessible sites within functionally important regions of Escherichia coli ligase (EC-LigA) were identified using in silico methods. Molecular docking was then used to screen for small molecules predicted to bind to these sites. Eight candidate inhibitors were then screened for inhibitory activity in an in vitro ligase assay. Five of these (geneticin, chlorhexidine, glutathione (reduced), imidazolidinyl urea and 2-(aminomethyl)imidazole) showed dose-dependent inhibition of EC-LigA with half maximal inhibitory concentrations (IC50) in the micromolar to millimolar range (11-2600 μM). Two (geneticin and chlorhexidine) were predicted to bind to a region of EC-LigA that has not been directly investigated previously, raising the possibility that there may be amino acids within this region that are important for EC-LigA activity or that the function of essential residues proximal to this region are impacted by inhibitor interactions with this region. We anticipate that the identified small molecule binding sites and inhibitors could be pursued as part of an antibacterial strategy targeting bacterial DNA ligases.

KW - RCUK

KW - BBSRC

KW - BB/J016179/1

U2 - 10.3390/molecules26092508

DO - 10.3390/molecules26092508

M3 - Article

VL - 26

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 9

M1 - 2508

ER -

ID: 27290178