Lectin A (LecA) from Pseudomonas aeruginosa is an established virulence factor. Glycoclusters that target LecA and are able to compete with human glycoconjugates present on epithelial cells are promising candidates to treat P. aeruginosa infection. A family of 32 glycodendrimers of generation 0 and 1 based on a bifurcated bis-galactoside motif have been designed to interact with LecA. The influences both of the central multivalent core and of the aglycon of these glycodendrimers on their affinity toward LecA have been evaluated by use of a microarray technique, both qualitatively for rapid screening of the binding properties and also quantitatively (K ). This has led to high-affinity LecA ligands with K values in the low nanomolar range (K =22 nm for the best one).

Due to the ability of Pseudomonas aeruginosa (PA) to develop antibiotic resistances, alternative therapeutic strategies have been proposed. Among others, carbohydrate multivalent molecules targeting lectin‐based virulent factors have been widely reported in particular those targeting LecA. LecA is a tetravalent galactose specific lectin involved in biofilm formation and cell internalization. Herein, we report the synthesis of 36 galactoclusters built from galactosides with aromatic and non‐aromatic aglycons and with an additional chain. The chains were either neutral or positively charged. Only the galactoclusters with naphthyl or tyrosine aglycon showed a moderate increase of binding for the positively charged 3‐dimethylammonium propyl chain. In contrast, the non‐aromatic galactoclusters display typically poorer binding properties towards LecA. The introduction of these side chains led to improved affinities up to becoming comparable to the high‐affinity aromatic galactoclusters.

Galacto-and fuco-clusters conjugated with one to three catechol or hydroxamate motifs were synthesised to target LecA and LecB lectins of Pseudomonas aeruginosa (PA) localised in the outer membrane and inside the bacterium. The resulting glycocluster-pseudosiderophore conjugates were evaluated as Trojan horses to cross the outer membrane of PA by iron transport. The data suggest that glycoclusters with catechol moieties are able to hijack the iron transport, whereas those with hydroxamates showed strong nonspecific interactions. Mono-and tricatechol galactoclusters (G1C and G3C) were evaluated as inhibitors of infection by PA in comparison with the free galactocluster (G0). All of them exhibited an inhibitory effect between 46 to 75 % at 100 μM, with a higher potency than G0. This result shows that LecA localised in the outer membrane of PA is involved in the infection mechanism.

Methylthioethanol and 2,2′‐thiodiethanol were derivatized into cyanoethyl‐phosphoramidites and solid support and were used to synthesize 5′‐, 3′‐monophosphate or 5′‐, 3′‐monothiophosphate oligonucleotides by thermolytic treatment followed by ammonia. The corresponding 2,2′‐thiodiethanol solid support was also used to release fully protected oligonucleotides from solid support without ammonia treatment, to monitor the oligonucleotide elongation on solid support by MALDI‐TOF mass spectrometry without any prior chemical treatment or to synthesize 3′‐pentynyl oligonucleotides in combination with a modified phosphoramidite where the cyanoethyl group was replaced by a pentynyl one.

Arrangements formed by the lectin LecA and five different synthetic glycoclusters were studied by AFM imaging combined to MD simulations. Arrangements and affinities differ depending on the nature of the core and the branches of the glycoclusters.