Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases
The Mur ligases form a series of consecutive enzymes that participate in the intracellular steps of bacterial peptidoglycan biosynthesis. They therefore represent interesting targets for antibacterial drug discovery. MurC, D, E and F are all ATP-dependent ligases. Accordingly, with the aim being to...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2019-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2019.1608981 |
| _version_ | 1811233093372084224 |
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| author | Martina Hrast Kaja Rožman Iza Ogris Veronika Škedelj Delphine Patin Matej Sova Hélène Barreteau Stanislav Gobec Simona Golič Grdadolnik Anamarija Zega |
| author_facet | Martina Hrast Kaja Rožman Iza Ogris Veronika Škedelj Delphine Patin Matej Sova Hélène Barreteau Stanislav Gobec Simona Golič Grdadolnik Anamarija Zega |
| author_sort | Martina Hrast |
| collection | DOAJ |
| description | The Mur ligases form a series of consecutive enzymes that participate in the intracellular steps of bacterial peptidoglycan biosynthesis. They therefore represent interesting targets for antibacterial drug discovery. MurC, D, E and F are all ATP-dependent ligases. Accordingly, with the aim being to find multiple inhibitors of these enzymes, we screened a collection of ATP-competitive kinase inhibitors, on Escherichia coli MurC, D and F, and identified five promising scaffolds that inhibited at least two of these ligases. Compounds 1, 2, 4 and 5 are multiple inhibitors of the whole MurC to MurF cascade that act in the micromolar range (IC50, 32–368 µM). NMR-assisted binding studies and steady-state kinetics studies performed on aza-stilbene derivative 1 showed, surprisingly, that it acts as a competitive inhibitor of MurD activity towards D-glutamic acid, and additionally, that its binding to the D-glutamic acid binding site is independent of the enzyme closure promoted by ATP. |
| first_indexed | 2024-04-12T11:15:46Z |
| format | Article |
| id | doaj.art-611a82a2fe88425aaa24c3fa2a9502bd |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-12T11:15:46Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-611a82a2fe88425aaa24c3fa2a9502bd2022-12-22T03:35:30ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742019-01-013411010101710.1080/14756366.2019.16089811608981Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligasesMartina Hrast0Kaja Rožman1Iza Ogris2Veronika Škedelj3Delphine Patin4Matej Sova5Hélène Barreteau6Stanislav Gobec7Simona Golič Grdadolnik8Anamarija Zega9University of LjubljanaUniversity of LjubljanaNational Institute of ChemistryUniversity of LjubljanaInstitute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-SaclayUniversity of LjubljanaInstitute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-SaclayUniversity of LjubljanaNational Institute of ChemistryUniversity of LjubljanaThe Mur ligases form a series of consecutive enzymes that participate in the intracellular steps of bacterial peptidoglycan biosynthesis. They therefore represent interesting targets for antibacterial drug discovery. MurC, D, E and F are all ATP-dependent ligases. Accordingly, with the aim being to find multiple inhibitors of these enzymes, we screened a collection of ATP-competitive kinase inhibitors, on Escherichia coli MurC, D and F, and identified five promising scaffolds that inhibited at least two of these ligases. Compounds 1, 2, 4 and 5 are multiple inhibitors of the whole MurC to MurF cascade that act in the micromolar range (IC50, 32–368 µM). NMR-assisted binding studies and steady-state kinetics studies performed on aza-stilbene derivative 1 showed, surprisingly, that it acts as a competitive inhibitor of MurD activity towards D-glutamic acid, and additionally, that its binding to the D-glutamic acid binding site is independent of the enzyme closure promoted by ATP.http://dx.doi.org/10.1080/14756366.2019.1608981bacterial mur (murc–murf) ligasespublished kinase inhibitor setsteady-state kinetics measurementsnmr studiesantibacterial agents |
| spellingShingle | Martina Hrast Kaja Rožman Iza Ogris Veronika Škedelj Delphine Patin Matej Sova Hélène Barreteau Stanislav Gobec Simona Golič Grdadolnik Anamarija Zega Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases Journal of Enzyme Inhibition and Medicinal Chemistry bacterial mur (murc–murf) ligases published kinase inhibitor set steady-state kinetics measurements nmr studies antibacterial agents |
| title | Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases |
| title_full | Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases |
| title_fullStr | Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases |
| title_full_unstemmed | Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases |
| title_short | Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases |
| title_sort | evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial atp dependent mur ligases |
| topic | bacterial mur (murc–murf) ligases published kinase inhibitor set steady-state kinetics measurements nmr studies antibacterial agents |
| url | http://dx.doi.org/10.1080/14756366.2019.1608981 |
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