Summary for 6Z07
| Entry DOI | 10.2210/pdb6z07/pdb |
| Related | 6YZ3 |
| Descriptor | Transcriptional regulator MvfR, 3-[(2-~{tert}-butyl-1,3-thiazol-4-yl)methyl]-6-chloranyl-quinazolin-4-one, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | pseudomonas aeruginosa, antagonist, quorum sensing, dna binding protein |
| Biological source | Pseudomonas aeruginosa (strain UCBPP-PA14) |
| Total number of polymer chains | 1 |
| Total formula weight | 27175.13 |
| Authors | Richardson, W.K.,Emsley, J. (deposition date: 2020-05-07, release date: 2020-09-16, Last modification date: 2024-01-24) |
| Primary citation | Grossman, S.,Soukarieh, F.,Richardson, W.,Liu, R.,Mashabi, A.,Emsley, J.,Williams, P.,Camara, M.,Stocks, M.J. Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR. Eur.J.Med.Chem., 208:112778-112778, 2020 Cited by PubMed Abstract: Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target. We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC < 300 nM) in a whole-cell assay, using a mCTX:P-lux-based bioreporter for the P. aeruginosa PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one (18) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3H)-one (19) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds 18 and 19 showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation. PubMed: 32927392DOI: 10.1016/j.ejmech.2020.112778 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.95 Å) |
Structure validation
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