Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein–Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay Evaluation
Quorum sensing (QS) is a cell-to-cell communication mechanism that regulates bacterial pathogenicity, biofilm formation, and antibiotic sensitivity. Among the identified quorum sensing, AI-2 QS exists in both Gram-negative and Gram-positive bacteria and is responsible for interspecies communication....
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/5/737 |
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| author | Yijie Xu Chunlan Zeng Huiqi Wen Qianqian Shi Xu Zhao Qingbin Meng Xingzhou Li Junhai Xiao |
| author_facet | Yijie Xu Chunlan Zeng Huiqi Wen Qianqian Shi Xu Zhao Qingbin Meng Xingzhou Li Junhai Xiao |
| author_sort | Yijie Xu |
| collection | DOAJ |
| description | Quorum sensing (QS) is a cell-to-cell communication mechanism that regulates bacterial pathogenicity, biofilm formation, and antibiotic sensitivity. Among the identified quorum sensing, AI-2 QS exists in both Gram-negative and Gram-positive bacteria and is responsible for interspecies communication. Recent studies have highlighted the connection between the phosphotransferase system (PTS) and AI-2 QS, with this link being associated with protein-protein interaction (PPI) between HPr and LsrK. Here, we first discovered several AI-2 QSIs targeting the LsrK/HPr PPI site through molecular dynamics (MD) simulation, virtual screening, and bioassay evaluation. Of the 62 compounds purchased, eight compounds demonstrated significant inhibition in LsrK-based assays and AI-2 QS interference assays. Surface plasmon resonance (SPR) analysis confirmed that the hit compound 4171-0375 specifically bound to the LsrK-N protein (HPr binding domain, KD = 2.51 × 10<sup>−5</sup> M), and therefore the LsrK/HPr PPI site. The structure-activity relationships (SARs) emphasized the importance of hydrophobic interactions with the hydrophobic pocket and hydrogen bonds or salt bridges with key residues of LsrK for LsrK/HPr PPI inhibitors. These new AI-2 QSIs, especially 4171-0375, exhibited novel structures, significant LsrK inhibition, and were suitable for structural modification to search for more effective AI-2 QSIs. |
| first_indexed | 2024-03-11T03:25:55Z |
| format | Article |
| id | doaj.art-e5f3a2f0ae4a48e6b974fce27ba5882d |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T03:25:55Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-e5f3a2f0ae4a48e6b974fce27ba5882d2023-11-18T02:49:12ZengMDPI AGPharmaceuticals1424-82472023-05-0116573710.3390/ph16050737Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein–Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay EvaluationYijie Xu0Chunlan Zeng1Huiqi Wen2Qianqian Shi3Xu Zhao4Qingbin Meng5Xingzhou Li6Junhai Xiao7National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaState Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, ChinaNational Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaDepartment of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaQuorum sensing (QS) is a cell-to-cell communication mechanism that regulates bacterial pathogenicity, biofilm formation, and antibiotic sensitivity. Among the identified quorum sensing, AI-2 QS exists in both Gram-negative and Gram-positive bacteria and is responsible for interspecies communication. Recent studies have highlighted the connection between the phosphotransferase system (PTS) and AI-2 QS, with this link being associated with protein-protein interaction (PPI) between HPr and LsrK. Here, we first discovered several AI-2 QSIs targeting the LsrK/HPr PPI site through molecular dynamics (MD) simulation, virtual screening, and bioassay evaluation. Of the 62 compounds purchased, eight compounds demonstrated significant inhibition in LsrK-based assays and AI-2 QS interference assays. Surface plasmon resonance (SPR) analysis confirmed that the hit compound 4171-0375 specifically bound to the LsrK-N protein (HPr binding domain, KD = 2.51 × 10<sup>−5</sup> M), and therefore the LsrK/HPr PPI site. The structure-activity relationships (SARs) emphasized the importance of hydrophobic interactions with the hydrophobic pocket and hydrogen bonds or salt bridges with key residues of LsrK for LsrK/HPr PPI inhibitors. These new AI-2 QSIs, especially 4171-0375, exhibited novel structures, significant LsrK inhibition, and were suitable for structural modification to search for more effective AI-2 QSIs.https://www.mdpi.com/1424-8247/16/5/737AI-2quorum sensingantibacterial agentsLsrKvirtual screeningmolecular dynamics |
| spellingShingle | Yijie Xu Chunlan Zeng Huiqi Wen Qianqian Shi Xu Zhao Qingbin Meng Xingzhou Li Junhai Xiao Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein–Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay Evaluation Pharmaceuticals AI-2 quorum sensing antibacterial agents LsrK virtual screening molecular dynamics |
| title | Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein–Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay Evaluation |
| title_full | Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein–Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay Evaluation |
| title_fullStr | Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein–Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay Evaluation |
| title_full_unstemmed | Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein–Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay Evaluation |
| title_short | Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein–Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay Evaluation |
| title_sort | discovery of ai 2 quorum sensing inhibitors targeting the lsrk hpr protein protein interaction site by molecular dynamics simulation virtual screening and bioassay evaluation |
| topic | AI-2 quorum sensing antibacterial agents LsrK virtual screening molecular dynamics |
| url | https://www.mdpi.com/1424-8247/16/5/737 |
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