Flexible Fragment Growing Boosts Potency of Quorum-Sensing Inhibitors against Pseudomonas aeruginosa Virulence.

Autor: Zender M; Drug Design and Optimization (DDOP), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123, Saarbrücken, Germany., Witzgall F; Structure and Function of Proteins (SFPR), Helmholtz Centre for Infection Research (HZI), Inhoffenstr. 7, 38124, Braunschweig, Germany., Kiefer A; Drug Design and Optimization (DDOP), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123, Saarbrücken, Germany., Kirsch B; Drug Design and Optimization (DDOP), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123, Saarbrücken, Germany., Maurer CK; Drug Design and Optimization (DDOP), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123, Saarbrücken, Germany., Kany AM; Drug Design and Optimization (DDOP), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123, Saarbrücken, Germany., Xu N; Lehrstuhl für Biochemie, Universität Bayreuth, Universitätsstr. 30, 95447, Bayreuth, Germany., Schmelz S; Structure and Function of Proteins (SFPR), Helmholtz Centre for Infection Research (HZI), Inhoffenstr. 7, 38124, Braunschweig, Germany., Börger C; PharmBioTec GmbH, Science Park 1, 66123, Saarbrücken, Germany., Blankenfeldt W; Structure and Function of Proteins (SFPR), Helmholtz Centre for Infection Research (HZI), Inhoffenstr. 7, 38124, Braunschweig, Germany.; Biotechnology and Bioinformatics, Institute for Biochemistry, Technische Universität Braunschweig, Spielmannstr. 7, 38106, Braunschweig, Germany., Empting M; Drug Design and Optimization (DDOP), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123, Saarbrücken, Germany.; Department of Pharmacy, Saarland University, Campus E8.1, 66123, Saarbrücken, Germany.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2020 Jan 17; Vol. 15 (2), pp. 188-194. Date of Electronic Publication: 2019 Nov 28.
DOI: 10.1002/cmdc.201900621
Abstrakt: Hit-to-lead optimization is a critical phase in drug discovery. Herein, we report on the fragment-based discovery and optimization of 2-aminopyridine derivatives as a novel lead-like structure for the treatment of the dangerous opportunistic pathogen Pseudomonas aeruginosa. We pursue an innovative treatment strategy by interfering with the Pseudomonas quinolone signal (PQS) quorum sensing (QS) system leading to an abolishment of bacterial pathogenicity. Our compounds act on the PQS receptor (PqsR), a key transcription factor controlling the expression of various pathogenicity determinants. In this target-driven approach, we made use of biophysical screening via surface plasmon resonance (SPR) followed by isothermal titration calorimetry (ITC)-enabled enthalpic efficiency (EE) evaluation. Hit optimization then involved growth vector identification and exploitation. Astonishingly, the latter was successfully achieved by introducing flexible linkers rather than rigid motifs leading to a boost in activity on the target receptor and anti-virulence potency.
(© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)
Databáze: MEDLINE
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