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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| Main Authors: | , , , , , , , |
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| Format: | Book |
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MDPI AG,
2023-05-01T00:00:00Z.
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| LEADER | 00000 am a22000003u 4500 | ||
|---|---|---|---|
| 001 | doaj_e5f3a2f0ae4a48e6b974fce27ba5882d | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Yijie Xu |e author |
| 700 | 1 | 0 | |a Chunlan Zeng |e author |
| 700 | 1 | 0 | |a Huiqi Wen |e author |
| 700 | 1 | 0 | |a Qianqian Shi |e author |
| 700 | 1 | 0 | |a Xu Zhao |e author |
| 700 | 1 | 0 | |a Qingbin Meng |e author |
| 700 | 1 | 0 | |a Xingzhou Li |e author |
| 700 | 1 | 0 | |a Junhai Xiao |e author |
| 245 | 0 | 0 | |a Discovery of AI-2 Quorum Sensing Inhibitors Targeting the LsrK/HPr Protein-Protein Interaction Site by Molecular Dynamics Simulation, Virtual Screening, and Bioassay Evaluation |
| 260 | |b MDPI AG, |c 2023-05-01T00:00:00Z. | ||
| 500 | |a 10.3390/ph16050737 | ||
| 500 | |a 1424-8247 | ||
| 520 | |a 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. | ||
| 546 | |a EN | ||
| 690 | |a AI-2 | ||
| 690 | |a quorum sensing | ||
| 690 | |a antibacterial agents | ||
| 690 | |a LsrK | ||
| 690 | |a virtual screening | ||
| 690 | |a molecular dynamics | ||
| 690 | |a Medicine | ||
| 690 | |a R | ||
| 690 | |a Pharmacy and materia medica | ||
| 690 | |a RS1-441 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Pharmaceuticals, Vol 16, Iss 5, p 737 (2023) | |
| 787 | 0 | |n https://www.mdpi.com/1424-8247/16/5/737 | |
| 787 | 0 | |n https://doaj.org/toc/1424-8247 | |
| 856 | 4 | 1 | |u https://doaj.org/article/e5f3a2f0ae4a48e6b974fce27ba5882d |z Connect to this object online. |