TY - JOUR

T1 - Glycomimetic, Orally Bioavailable LecB Inhibitors Block Biofilm Formation of Pseudomonas aeruginosa

AU - Sommer, Roman

AU - Wagner, Stefanie

AU - Rox, Katharina

AU - Varrot, Annabelle

AU - Hauck, Dirk

AU - Wamhoff, Eike Christian

AU - Schreiber, Janine

AU - Ryckmans, Thomas

AU - Brunner, Thomas

AU - Rademacher, Christoph

AU - Hartmann, Rolf W.

AU - Brönstrup, Mark

AU - Imberty, Anne

AU - Titz, Alexander

N1 - Funding Information: We are grateful to Sarah Henrikus and Shelby Newsad for chemistry support and to Dr. Michael Hoffmann for HRMS measurements (all HIPS Saarbrücken). We acknowledge technical assistance from Tatjana Arnold (HZI, Braunschweig) and Astrid Glöckner (Konstanz University); Dr. Aymeric Audfray (CERMAV Grenoble) is acknowledged for instructions to SPR. We thank Dr. Josef Zapp (Saarland University) for performing NMR measurements. Crystal data collection was performed at the European Synchrotron Radiation Facility, Grenoble, France, and we are grateful for access and technical support to beamline FIP-BM30A and ID29. A.I. and A.V. acknowledge support from the ANR projects Glyco@Alps (ANR-15-IDEX-02) and Labex ARCANE (ANR-11-LABX-003). We thank the Helmholtz Association (grant no VH-NG-934, to A.T.), EU COST action BM1003 (to R.S.), DAAD RISE program (to S. Newsad and R.S.) and the Deutsche Forschungsgemeinschaft (to A.T., grant no. Ti756/2-1, to C.R., grant no. RA1944/2-1) for financial support.

PY - 2018/2/21

Y1 - 2018/2/21

N2 - The opportunistic Gram-negative bacterium Pseudomonas aeruginosa is a leading pathogen for infections of immuno-compromised patients and those suffering from cystic fibrosis. Its ability to switch from planktonic life to aggregates, forming the so-called biofilms, is a front-line mechanism of antimicrobial resistance. The bacterial carbohydrate-binding protein LecB is an integral component and necessary for biofilm formation. Here, we report a new class of drug-like low molecular weight inhibitors of the lectin LecB with nanomolar affinities and excellent receptor binding kinetics and thermodynamics. This class of glycomimetic inhibitors efficiently blocked biofilm formation of P. aeruginosa in vitro while the natural monovalent carbohydrate ligands failed. Furthermore, excellent selectivity and pharmacokinetic properties were achieved. Notably, two compounds showed good oral bioavailability, and high compound concentrations in plasma and urine were achieved in vivo.

AB - The opportunistic Gram-negative bacterium Pseudomonas aeruginosa is a leading pathogen for infections of immuno-compromised patients and those suffering from cystic fibrosis. Its ability to switch from planktonic life to aggregates, forming the so-called biofilms, is a front-line mechanism of antimicrobial resistance. The bacterial carbohydrate-binding protein LecB is an integral component and necessary for biofilm formation. Here, we report a new class of drug-like low molecular weight inhibitors of the lectin LecB with nanomolar affinities and excellent receptor binding kinetics and thermodynamics. This class of glycomimetic inhibitors efficiently blocked biofilm formation of P. aeruginosa in vitro while the natural monovalent carbohydrate ligands failed. Furthermore, excellent selectivity and pharmacokinetic properties were achieved. Notably, two compounds showed good oral bioavailability, and high compound concentrations in plasma and urine were achieved in vivo.

UR - http://www.scopus.com/inward/record.url?scp=85042348356&partnerID=8YFLogxK

U2 - 10.1021/jacs.7b11133

DO - 10.1021/jacs.7b11133

M3 - Article

C2 - 29272578

AN - SCOPUS:85042348356

VL - 140

SP - 2537

EP - 2545

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 7

ER -