Monodisperse Sequence‐Controlled α‐l‐Fucosylated Glycooligomers and Their Multivalent Inhibitory Effects on LecB

Abstract

The opportunistic bacterium Pseudomonas aeruginosa, often exhibiting multiresistance against conventional antibiotics, expresses the lectin LecB that is suspected to be an important factor during biofilm formation via interactions with cell‐surface presented carbohydrate ligands such as the blood group antigens. Therefore, carbohydrate‐based ligands interfering with LecB binding have the potential to lead to new anti‐biofilm and anti‐adhesion therapies. This study explores in vitro binding potencies of glycomimetic ligands containing up to six α‐l‐fucose ligands on a monodisperse, sequence‐controlled oligoamide scaffold interacting with LecB. Surface plasmon resonance (SPR) and a modified enzyme‐linked lectin assay (mELLA) revealed an increasing affinity to LecB with increasing fucose valency. Furthermore, fucosylated glycooligomers were shown to inhibit the formation of P. aeruginosa biofilm up to 20%. Overall these results show the potential of fucosylated oligoamides to be further developed as inhibitors of LecB binding and biofilm formation.

Genetically Encoded Photosensitizers as Light-Triggered Antimicrobial Agents

“…To evaluate, if the extracellular phototoxicity of a protein-encased PS can be enhanced by specifically directing it to the bacterial cell envelope, we fused DsFbFP M49I, which exhibits the highest extracellular phototoxicity for the human pathogen P. aeruginosa, to the lectin LecB (Figure 5a). LecB is a multivalent sugar-binding protein derived from P. aeruginosa that is naturally formed by the bacterium for biofilm formation and initiation of human infections [58,59,60]. This lectin can bind to various sugar moieties located on the surface of P. aeruginosa cells [61,62] and it was recently published that LecB immobilized on the surface of hydrogels can be used to efficiently capture P. aeruginosa cells for their treatment with antimicrobial peptides [63].…”

Glycopeptides and -Mimetics to Detect, Monitor and Inhibit Bacterial and Viral Infections: Recent Advances and Perspectives

“…In one study, fucosylated glycooligomers were synthesized and their inhibition potential towards LecB of Pseudomonas aeruginosa and biofilm formation was explored. The sequence-controlled α- l -fucose-functionalized glycooligomers were assembled via alternating coupling of above mentioned building blocks EDS and TDS using SPPoS (Figure 6a) [55]. Fucosylated glycooligomers with valencies ranging from one to six carbohydrate ligands, and trivalent derivatives with one, two, or three EDS spacers between the fucose-functionalized TDS building blocks were prepared.…”

“…So far, knowledge about the mechanism of the ligand-virus interaction is limited and it is not clear, if a multivalent fucose-functionalized ligand simultaneously can bind all four binding pockets. In work from Hartmann et al multivalent fucosylated precision macromolecules were synthesized according to the previously mentioned protocol [55] and their ability to bind to NoV P-dimers were investigated by native MS, STD NMR, and X-ray crystallography experiments (Figure 17) [136]. Precision glycomacromolecules carrying varying numbers of fucose ligands, and exhibiting different spacing between the ligands on the oligomeric backbone were prepared via SPPoS.…”

Modified Galacto‐ or Fuco‐Clusters Exploiting the Siderophore Pathway to Inhibit the LecA‐ or LecB‐Associated Virulence of Pseudomonas aeruginosa

“…To date, several glycoclusters, presenting strong affinity for these two targets, have been reported in the literature [8] and some of them demonstrated some in vivo activity against PA especially antibiofilm property [8b,c,d,i,j,9] and anti‐bacterial adhesion [8f,h,10] …”