Structural Insights into the Ligand–LsrK Kinase Binding Mode: A Step Forward in the Discovery of Novel Antimicrobial Agents
LsrK is a bacterial kinase that triggers the quorum sensing, and it represents a druggable target for the identification of new agents for fighting antimicrobial resistance. Herein, we exploited tryptophan fluorescence spectroscopy (TFS) as a suitable technique for the identification of potential Ls...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/6/2542 |
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| author | Roberta Listro Giorgio Milli Angelica Pellegrini Chiara Motta Valeria Cavalloro Emanuela Martino Johannes Kirchmair Giampiero Pietrocola Daniela Rossi Pasquale Linciano Simona Collina |
| author_facet | Roberta Listro Giorgio Milli Angelica Pellegrini Chiara Motta Valeria Cavalloro Emanuela Martino Johannes Kirchmair Giampiero Pietrocola Daniela Rossi Pasquale Linciano Simona Collina |
| author_sort | Roberta Listro |
| collection | DOAJ |
| description | LsrK is a bacterial kinase that triggers the quorum sensing, and it represents a druggable target for the identification of new agents for fighting antimicrobial resistance. Herein, we exploited tryptophan fluorescence spectroscopy (TFS) as a suitable technique for the identification of potential LsrK ligands from an in-house library of chemicals comprising synthetic compounds as well as secondary metabolites. Three secondary metabolites (<b>Hib-ester</b>, <b>Hib-carbaldehyde</b> and <b>(<i>R</i>)-ASME</b>) showed effective binding to LsrK, with KD values in the sub-micromolar range. The conformational changes were confirmed via circular dichroism and molecular docking results further validated the findings and displayed the specific mode of interaction. The activity of the identified compounds on the biofilm formation by some <i>Staphylococcus</i> spp. was investigated. <b>Hib-carbaldehyde</b> and <b>(<i>R</i>)-ASME</b> were able to reduce the production of biofilm, with <b>(<i>R</i>)-ASME</b> resulting in the most effective compound with an EC<sub>50</sub> of 14 mg/well. The successful application of TFS highlights its usefulness in searching for promising LsrK inhibitor candidates with inhibitor efficacy against biofilm formation. |
| first_indexed | 2024-03-11T06:07:20Z |
| format | Article |
| id | doaj.art-67682f09164b4806981cc8afc3cd4671 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T06:07:20Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-67682f09164b4806981cc8afc3cd46712023-11-17T12:51:46ZengMDPI AGMolecules1420-30492023-03-01286254210.3390/molecules28062542Structural Insights into the Ligand–LsrK Kinase Binding Mode: A Step Forward in the Discovery of Novel Antimicrobial AgentsRoberta Listro0Giorgio Milli1Angelica Pellegrini2Chiara Motta3Valeria Cavalloro4Emanuela Martino5Johannes Kirchmair6Giampiero Pietrocola7Daniela Rossi8Pasquale Linciano9Simona Collina10Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, ItalyDepartment of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, ItalyDepartment of Molecular Medicine, Biochemistry Unit, University of Pavia, Viale Taramelli 3/b, 27100 Pavia, ItalyDepartment of Molecular Medicine, Biochemistry Unit, University of Pavia, Viale Taramelli 3/b, 27100 Pavia, ItalyDepartment of Earth and Environmental Sciences, University of Pavia, Via Sant ’Epifanio 14, 27100 Pavia, ItalyDepartment of Earth and Environmental Sciences, University of Pavia, Via Sant ’Epifanio 14, 27100 Pavia, ItalyDivision of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 2D 303, 1090 Vienna, AustriaDepartment of Molecular Medicine, Biochemistry Unit, University of Pavia, Viale Taramelli 3/b, 27100 Pavia, ItalyDepartment of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, ItalyDepartment of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, ItalyDepartment of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, ItalyLsrK is a bacterial kinase that triggers the quorum sensing, and it represents a druggable target for the identification of new agents for fighting antimicrobial resistance. Herein, we exploited tryptophan fluorescence spectroscopy (TFS) as a suitable technique for the identification of potential LsrK ligands from an in-house library of chemicals comprising synthetic compounds as well as secondary metabolites. Three secondary metabolites (<b>Hib-ester</b>, <b>Hib-carbaldehyde</b> and <b>(<i>R</i>)-ASME</b>) showed effective binding to LsrK, with KD values in the sub-micromolar range. The conformational changes were confirmed via circular dichroism and molecular docking results further validated the findings and displayed the specific mode of interaction. The activity of the identified compounds on the biofilm formation by some <i>Staphylococcus</i> spp. was investigated. <b>Hib-carbaldehyde</b> and <b>(<i>R</i>)-ASME</b> were able to reduce the production of biofilm, with <b>(<i>R</i>)-ASME</b> resulting in the most effective compound with an EC<sub>50</sub> of 14 mg/well. The successful application of TFS highlights its usefulness in searching for promising LsrK inhibitor candidates with inhibitor efficacy against biofilm formation.https://www.mdpi.com/1420-3049/28/6/2542LsrKantimicrobial resistancetryptophan fluorescence spectroscopycircular dichroismdockingscreening |
| spellingShingle | Roberta Listro Giorgio Milli Angelica Pellegrini Chiara Motta Valeria Cavalloro Emanuela Martino Johannes Kirchmair Giampiero Pietrocola Daniela Rossi Pasquale Linciano Simona Collina Structural Insights into the Ligand–LsrK Kinase Binding Mode: A Step Forward in the Discovery of Novel Antimicrobial Agents Molecules LsrK antimicrobial resistance tryptophan fluorescence spectroscopy circular dichroism docking screening |
| title | Structural Insights into the Ligand–LsrK Kinase Binding Mode: A Step Forward in the Discovery of Novel Antimicrobial Agents |
| title_full | Structural Insights into the Ligand–LsrK Kinase Binding Mode: A Step Forward in the Discovery of Novel Antimicrobial Agents |
| title_fullStr | Structural Insights into the Ligand–LsrK Kinase Binding Mode: A Step Forward in the Discovery of Novel Antimicrobial Agents |
| title_full_unstemmed | Structural Insights into the Ligand–LsrK Kinase Binding Mode: A Step Forward in the Discovery of Novel Antimicrobial Agents |
| title_short | Structural Insights into the Ligand–LsrK Kinase Binding Mode: A Step Forward in the Discovery of Novel Antimicrobial Agents |
| title_sort | structural insights into the ligand lsrk kinase binding mode a step forward in the discovery of novel antimicrobial agents |
| topic | LsrK antimicrobial resistance tryptophan fluorescence spectroscopy circular dichroism docking screening |
| url | https://www.mdpi.com/1420-3049/28/6/2542 |
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