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Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa

Soukarieh, Fadi (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.;Univ Nottingham, Natl Biofilms Innovat Ctr, Nottingham, England.
Liu, Ruiling (författare)
Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England.
Romero, Manuel (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.;Univ Nottingham, Natl Biofilms Innovat Ctr, Nottingham, England.
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Roberston, Shaun N. (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.;Univ Nottingham, Natl Biofilms Innovat Ctr, Nottingham, England.
Richardson, William (författare)
Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England.
Lucanto, Simone (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.;Univ Nottingham, Natl Biofilms Innovat Ctr, Nottingham, England.
Oton, Eduard Vico (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.
Qudus, Naim Ruhul (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.
Mashabi, Alaa (författare)
Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England.
Grossman, Scott (författare)
Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England.
Ali, Sadiqur (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.
Sou, Tomás (författare)
Uppsala universitet,Institutionen för farmaci,Institutionen för farmaceutisk biovetenskap
Kukavica-Ibrulj, Irena (författare)
Univ Laval, Inst Biol Integrat & Syst, Quebec City, PQ, Canada.
Levesque, Roger C. (författare)
Univ Laval, Inst Biol Integrat & Syst, Quebec City, PQ, Canada.
Bergström, Christel, 1973- (författare)
Uppsala universitet,Institutionen för farmaci
Halliday, Nigel (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.
Mistry, Shailesh N. (författare)
Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England.
Emsley, Jonas (författare)
Univ Nottingham, Natl Biofilms Innovat Ctr, Nottingham, England.;Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England.
Heeb, Stephan (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.
Williams, Paul (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.;Univ Nottingham, Natl Biofilms Innovat Ctr, Nottingham, England.
Camara, Miguel (författare)
Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England.;Univ Nottingham, Natl Biofilms Innovat Ctr, Nottingham, England.
Stocks, Michael J. (författare)
Univ Nottingham, Natl Biofilms Innovat Ctr, Nottingham, England.;Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England.
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Univ Nottingham, Biodiscovery Inst, Sch Life Sci, Nottingham, England;Univ Nottingham, Natl Biofilms Innovat Ctr, Nottingham, England. Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England. (creator_code:org_t)
2020-05-04
2020
Engelska.
Ingår i: Frontiers in Chemistry. - : FRONTIERS MEDIA SA. - 2296-2646. ; 8
Relaterad länk:
https://doi.org/10.3...
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https://uu.diva-port... (primary) (Raw object)
https://www.frontier...
https://urn.kb.se/re...
https://doi.org/10.3...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • Current treatments for Pseudomonas aeruginosa infections are becoming less effective because of the increasing rates of multi-antibiotic resistance. Pharmacological targeting of virulence through inhibition of quorum sensing (QS) dependent virulence gene regulation has considerable therapeutic potential. In P. aeruginosa, the pqs QS system regulates the production of multiple virulence factors as well as biofilm maturation and is a promising approach for developing antimicrobial adjuvants for combatting drug resistance. In this work, we report the hit optimisation for a series of potent novel inhibitors of PqsR, a key regulator of the pqs system, bearing a 2-((5-methyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio) acetamide scaffold. The initial hit compound 7 (PAO1-L IC50 0.98 +/- 0.02 mu M, PA14 inactive at 10 mu M) was obtained through a virtual screening campaign performed on the PqsR ligand binding domain using the University of Nottingham Managed Chemical Compound Collection. Hit optimisation gave compounds with enhanced potency against strains PAO1-L and PA14, evaluated using P. aeruginosa pqs-based QS bioreporter assays. Compound 40 (PAO1-L IC50 0.25 +/- 0.12 mu M, PA14 IC50 0.34 +/- 0.03 mu M) is one of the most potent PqsR antagonists reported showing significant inhibition of P. aeruginosa pyocyanin production and pqs system signaling in both planktonic cultures and biofilms. The co-crystal structure of 40 with the PqsR ligand binding domain revealed the specific binding interactions occurring between inhibitor and this key regulatory protein.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

Pseudomonas aeruginosa
PqsR
MvfR
Pseudomonas quinolone signal (PQS)
alkylquinolone
biofilms
quorum sensing inhibition
quorum quenching

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