6YIZ

Crystal structure of PqsR (MvfR) ligand-binding domain in complex with triazolo-pyridine inverse agonist A

Summary for 6YIZ

• Entry DOI: 10.2210/pdb6yiz/pdb
• Descriptor: Transcriptional regulator MvfR, 7-oxidanylidene-8-[2-(4-sulfonaphthalen-1-yl)hydrazinyl]-8~{H}-naphthalene-1,3-disulfonic acid, ~{N}-[[1-(4-phenoxyphenyl)-1,2,3-triazol-4-yl]methyl]-2-(trifluoromethyl)pyridin-4-amine, ... (5 entities in total)
• Functional Keywords: quorum sensing, lysr-type transcriptional regulator, pseudomonas, 2 quinolone signaling system, lttr, dna binding protein
• Biological source: Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)
• Total number of polymer chains: 2
• Total formula weight: 53328.29

Authors

Schmelz, S.,Blankenfeldt, W. (deposition date: 2020-04-01, release date: 2021-04-14, Last modification date: 2024-01-24)

Primary citation

Schutz, C.,Ho, D.K.,Hamed, M.M.,Abdelsamie, A.S.,Rohrig, T.,Herr, C.,Kany, A.M.,Rox, K.,Schmelz, S.,Siebenburger, L.,Wirth, M.,Borger, C.,Yahiaoui, S.,Bals, R.,Scrima, A.,Blankenfeldt, W.,Horstmann, J.C.,Christmann, R.,Murgia, X.,Koch, M.,Berwanger, A.,Loretz, B.,Hirsch, A.K.H.,Hartmann, R.W.,Lehr, C.M.,Empting, M.
A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms.
Adv Sci, 8:e2004369-e2004369, 2021

PubMed Abstract: Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) - a crucial transcriptional regulator serving major functions in PA virulence - can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry-driven hit-to-lead optimization and in-depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter-gene with IC values as low as 200 and 11 × 10 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI-tobramycin (Tob) combination against PA biofilms using a tailor-made squalene-derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32-fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker-mediated therapy against PA infections opening up avenues for preclinical development.

PubMed: 34165899
DOI: 10.1002/advs.202004369

Experimental method

X-RAY DIFFRACTION (2.163 Å)