6TPR

PqsR (MvfR) bound to inhibitory compound 40

Summary for 6TPR

• Entry DOI: 10.2210/pdb6tpr/pdb
• Descriptor: Transcriptional regulator MvfR, 2-[(5-methyl-[1,2,4]triazino[5,6-b]indol-3-yl)sulfanyl]-~{N}-(4-pyridin-2-yloxyphenyl)ethanamide (3 entities in total)
• Functional Keywords: pseudomonas aeruginosa, quorum sensing, dna binding protein
• Biological source: Pseudomonas aeruginosa UCBPP-PA14
• Total number of polymer chains: 1
• Total formula weight: 27191.69

Authors

Richardson, W.K.,Emsley, J. (deposition date: 2019-12-14, release date: 2020-05-13, Last modification date: 2024-01-24)

Primary citation

Soukarieh, F.,Liu, R.,Romero, M.,Roberston, S.N.,Richardson, W.,Lucanto, S.,Oton, E.V.,Qudus, N.R.,Mashabi, A.,Grossman, S.,Ali, S.,Sou, T.,Kukavica-Ibrulj, I.,Levesque, R.C.,Bergstrom, C.A.S.,Halliday, N.,Mistry, S.N.,Emsley, J.,Heeb, S.,Williams, P.,Camara, M.,Stocks, M.J.
Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm GrownPseudomonas aeruginosa.
Front Chem, 8:204-204, 2020

PubMed Abstract: Current treatments for 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 , the 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 system, bearing a 2-((5-methyl-5-[1,2,4]triazino[5,6-]indol-3-yl)thio) acetamide scaffold. The initial hit compound (PAO1-L IC 0.98 ± 0.02 μM, PA14 inactive at 10 μM) 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 -based QS bioreporter assays. Compound (PAO1-L IC 0.25 ± 0.12 μM, PA14 IC 0.34 ± 0.03 μM) is one of the most potent PqsR antagonists reported showing significant inhibition of pyocyanin production and system signaling in both planktonic cultures and biofilms. The co-crystal structure of with the PqsR ligand binding domain revealed the specific binding interactions occurring between inhibitor and this key regulatory protein.

PubMed: 32432073
DOI: 10.3389/fchem.2020.00204

Experimental method

X-RAY DIFFRACTION (3.2 Å)