Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa
[Display omitted] The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be ut...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2021-02, Vol.31, p.115967-115967, Article 115967 |
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| container_title | Bioorganic & medicinal chemistry |
| container_volume | 31 |
| creator | Sabir, Shekh Suresh, Dittu Subramoni, Sujatha Das, Theerthankar Bhadbhade, Mohan Black, David StC Rice, Scott A. Kumar, Naresh |
| description | [Display omitted]
The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be utilized as quorum sensing inhibitors to treat P. aeruginosa infections. In this study, we report the synthesis of novel thioether-linked dihydropyrrol-2-one (DHP) analogues as PqsR antagonists. Compound 7g containing a 2-mercaptopyridyl linkage effectively inhibited the pqs system with an IC50 of 32 µM in P. aeruginosa PAO1. Additionally, these inhibitors significantly reduced bacterial aggregation and biofilm formation without affecting planktonic growth. The molecular docking study suggest that these inhibitors bind with the ligand binding domain of the MvfR as a competitive antagonist. |
| doi_str_mv | 10.1016/j.bmc.2020.115967 |
| format | Article |
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The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be utilized as quorum sensing inhibitors to treat P. aeruginosa infections. In this study, we report the synthesis of novel thioether-linked dihydropyrrol-2-one (DHP) analogues as PqsR antagonists. Compound 7g containing a 2-mercaptopyridyl linkage effectively inhibited the pqs system with an IC50 of 32 µM in P. aeruginosa PAO1. Additionally, these inhibitors significantly reduced bacterial aggregation and biofilm formation without affecting planktonic growth. The molecular docking study suggest that these inhibitors bind with the ligand binding domain of the MvfR as a competitive antagonist.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2020.115967</identifier><identifier>PMID: 33434766</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Dihydropyrrol-2-one (DHP) analogues ; PqsR antagonist ; Pseudomonas aeruginosa ; Pseudomonas quinolone system ; Quorum sensing inhibitors</subject><ispartof>Bioorganic & medicinal chemistry, 2021-02, Vol.31, p.115967-115967, Article 115967</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-b77cba92b9c23b630f9757f020aa2ec29267bc0ec89c2ac4808bcd54f089bb643</citedby><cites>FETCH-LOGICAL-c353t-b77cba92b9c23b630f9757f020aa2ec29267bc0ec89c2ac4808bcd54f089bb643</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2020.115967$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27907,27908,45978</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33434766$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sabir, Shekh</creatorcontrib><creatorcontrib>Suresh, Dittu</creatorcontrib><creatorcontrib>Subramoni, Sujatha</creatorcontrib><creatorcontrib>Das, Theerthankar</creatorcontrib><creatorcontrib>Bhadbhade, Mohan</creatorcontrib><creatorcontrib>Black, David StC</creatorcontrib><creatorcontrib>Rice, Scott A.</creatorcontrib><creatorcontrib>Kumar, Naresh</creatorcontrib><title>Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be utilized as quorum sensing inhibitors to treat P. aeruginosa infections. In this study, we report the synthesis of novel thioether-linked dihydropyrrol-2-one (DHP) analogues as PqsR antagonists. Compound 7g containing a 2-mercaptopyridyl linkage effectively inhibited the pqs system with an IC50 of 32 µM in P. aeruginosa PAO1. Additionally, these inhibitors significantly reduced bacterial aggregation and biofilm formation without affecting planktonic growth. The molecular docking study suggest that these inhibitors bind with the ligand binding domain of the MvfR as a competitive antagonist.</description><subject>Dihydropyrrol-2-one (DHP) analogues</subject><subject>PqsR antagonist</subject><subject>Pseudomonas aeruginosa</subject><subject>Pseudomonas quinolone system</subject><subject>Quorum sensing inhibitors</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kE1rGzEYhEVoSBw3PyCXssde1tXXSit6KqH5gEBDcM9C0r5ry92VHGk34H9fGac95iQ0mhk0D0I3BK8IJuLbbmVHt6KYljtplJBnaEG44DVjinxCC6xEW-NWiUt0lfMOY0y5IhfokjHOuBRigd7WWx9h2kKqBx_-QFd1fnvoUtwfUopDTesYoDLBDHEzQ65Mrp5f80tRJrOJweepaBvjQ56Omrc-Tt5VCXJ5KkL1nGHu4hhDSRpI88aHmM1ndN6bIcP1-7lEv-9-rm8f6qdf94-3P55qxxo21VZKZ42iVjnKrGC4V7KRfRlsDAVHFRXSOgyuLQbjeItb67qG92W0tYKzJfp66t2n-Fr-P-nRZwfDYALEOWvKpWwwK4iKlZysLsWcE_R6n_xo0kETrI-49U4X3PqIW59wl8yX9_rZjtD9T_zjWwzfTwYoI988JJ2dh-Cg8wncpLvoP6j_C9TokxE</recordid><startdate>20210201</startdate><enddate>20210201</enddate><creator>Sabir, Shekh</creator><creator>Suresh, Dittu</creator><creator>Subramoni, Sujatha</creator><creator>Das, Theerthankar</creator><creator>Bhadbhade, Mohan</creator><creator>Black, David StC</creator><creator>Rice, Scott A.</creator><creator>Kumar, Naresh</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20210201</creationdate><title>Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa</title><author>Sabir, Shekh ; Suresh, Dittu ; Subramoni, Sujatha ; Das, Theerthankar ; Bhadbhade, Mohan ; Black, David StC ; Rice, Scott A. ; Kumar, Naresh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-b77cba92b9c23b630f9757f020aa2ec29267bc0ec89c2ac4808bcd54f089bb643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Dihydropyrrol-2-one (DHP) analogues</topic><topic>PqsR antagonist</topic><topic>Pseudomonas aeruginosa</topic><topic>Pseudomonas quinolone system</topic><topic>Quorum sensing inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sabir, Shekh</creatorcontrib><creatorcontrib>Suresh, Dittu</creatorcontrib><creatorcontrib>Subramoni, Sujatha</creatorcontrib><creatorcontrib>Das, Theerthankar</creatorcontrib><creatorcontrib>Bhadbhade, Mohan</creatorcontrib><creatorcontrib>Black, David StC</creatorcontrib><creatorcontrib>Rice, Scott A.</creatorcontrib><creatorcontrib>Kumar, Naresh</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sabir, Shekh</au><au>Suresh, Dittu</au><au>Subramoni, Sujatha</au><au>Das, Theerthankar</au><au>Bhadbhade, Mohan</au><au>Black, David StC</au><au>Rice, Scott A.</au><au>Kumar, Naresh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2021-02-01</date><risdate>2021</risdate><volume>31</volume><spage>115967</spage><epage>115967</epage><pages>115967-115967</pages><artnum>115967</artnum><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be utilized as quorum sensing inhibitors to treat P. aeruginosa infections. In this study, we report the synthesis of novel thioether-linked dihydropyrrol-2-one (DHP) analogues as PqsR antagonists. Compound 7g containing a 2-mercaptopyridyl linkage effectively inhibited the pqs system with an IC50 of 32 µM in P. aeruginosa PAO1. Additionally, these inhibitors significantly reduced bacterial aggregation and biofilm formation without affecting planktonic growth. The molecular docking study suggest that these inhibitors bind with the ligand binding domain of the MvfR as a competitive antagonist.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>33434766</pmid><doi>10.1016/j.bmc.2020.115967</doi><tpages>1</tpages></addata></record> |
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| subjects | Dihydropyrrol-2-one (DHP) analogues PqsR antagonist Pseudomonas aeruginosa Pseudomonas quinolone system Quorum sensing inhibitors |
| title | Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa |
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