The virulence factor LecB varies in clinical isolates: consequences for ligand binding and drug discovery

Chemical Science
Roman SommerAlexander Titz

Abstract

P. aeruginosa causes a substantial number of nosocomial infections and is the leading cause of death of cystic fibrosis patients. This Gram-negative bacterium is highly resistant against antibiotics and further protects itself by forming a biofilm. Moreover, a high genomic variability among clinical isolates complicates therapy. Its lectin LecB is a virulence factor and necessary for adhesion and biofilm formation. We analyzed the sequence of LecB variants in a library of clinical isolates and demonstrate that it can serve as a marker for strain family classification. LecB from the highly virulent model strain PA14 presents 13% sequence divergence with LecB from the well characterized PAO1 strain. These differences might result in differing ligand binding specificities and ultimately in reduced efficacy of drugs directed towards LecB. Despite several amino acid variations at the carbohydrate binding site, glycan array analysis showed a comparable binding pattern for both variants. A common high affinity ligand could be identified and after its chemoenzymatic synthesis verified in a competitive binding assay: an N-glycan presenting two blood group O epitopes (H-type 2 antigen). Molecular modeling of the complex suggests a bivale...Continue Reading

References

Jan 1, 1982·Methods in Enzymology·N Gilboa-Garber
Feb 4, 2003·Nature Reviews. Drug Discovery·David Davies
Aug 12, 2003·Journal of Molecular Biology·Remy LorisLode Wyns
Mar 23, 2004·Nucleic Acids Research·Robert C Edgar
Nov 26, 2004·Proceedings of the National Academy of Sciences of the United States of America·Ola BlixtJames C Paulson
May 13, 2006·Environmental Microbiology·Stephen P DiggleKlaus Winzer
Aug 22, 2007·Nature Chemical Biology·Anne E ClatworthyDeborah T Hung
Apr 19, 2008·The Journal of Infectious Diseases·Louis B Rice
Apr 22, 2008·Nucleic Acids Research·A DereeperO Gascuel
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jun 10, 2010·Journal of the American Chemical Society·David SchwefelValentin Wittmann
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Garib N MurshudovAlexei A Vagin
Apr 9, 2011·Nature·Matthew A Cooper, David Shlaes
Jul 13, 2011·Frontiers in Microbiology·Keith Poole
Nov 18, 2011·Science Translational Medicine·Corinne K CusumanoScott J Hultgren
Jan 4, 2012·FEMS Microbiology Reviews·Ethan E Mann, Daniel J Wozniak
Mar 20, 2012·Chemical Communications : Chem Comm·Francesca Pertici, Roland J Pieters
Jun 8, 2013·Journal of the American Chemical Society·Jonas EggerBeat Ernst
Sep 5, 2013·Proceedings of the National Academy of Sciences of the United States of America·Drew J SchwartzScott J Hultgren
Oct 2, 2013·Nature Reviews. Drug Discovery·Thomas BjarnsholtNiels Høiby
Nov 25, 2014·Journal of Medicinal Chemistry·Amine M BoukerbSébastien Vidal

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Citations

Nov 10, 2018·Beilstein Journal of Organic Chemistry·Matthew B CalvertAlexander Titz
Dec 10, 2019·MedChemComm·Pablo ValverdeAna Gimeno
Nov 28, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lucie DupinBenoît Darblade
Oct 4, 2017·The Journal of Biological Chemistry·Ghamdan BeshrAlexander Titz
May 18, 2019·Nature Communications·Daniel Passos da SilvaMatthew R Parsek
Sep 30, 2017·Angewandte Chemie·Stefanie WagnerAlexander Titz
Dec 19, 2020·Expert Opinion on Drug Discovery·Vishnu C DamalankaJames W Janetka
Aug 31, 2019·Current Opinion in Chemical Biology·Joscha MeiersAlexander Titz
Feb 23, 2020·International Journal of Biological Macromolecules·Felipe Baena GarciaMárcia Aparecida Sperança
Jun 14, 2021·Journal of Molecular Biology·Aliza Borenstein-KatzRon Diskin
Dec 23, 2017·Journal of the American Chemical Society·Roman SommerAlexander Titz
Aug 27, 2019·Journal of Medicinal Chemistry·Marwa TaouaiMohammed Benazza
Aug 4, 2018·Journal of Chemical Information and Modeling·Tamir DingjanElizabeth Yuriev
Jan 6, 2022·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Olga MetelkinaAlexander Titz

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Methods Mentioned

BETA
X-ray
dynamic light scattering
size exclusion chromatography
NMR

Software Mentioned

REFMAC5
PhyML
CCP4
Tripos
Graphpad Prism
MUSCLE
Certara
Microcal Origin
Coot
XDS

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