A Glycopeptide Dendrimer Inhibitor of the Galactose‐Specific Lectin LecA and of <i>Pseudomonas aeruginosa</i> Biofilms

Kadam, Rameshwar U.; Bergmann, Myriam; Hurley, Margaret M.; Garg, Divita; Cacciarini, Martina; Świderska, Magdalena; Nativi, Cristina; Sattler, Michael; Smyth, Alan; Williams, Paul; Cámara, Miguel; Stocker, Achim; Darbre, Tamis; Reymond, Jean‐Louis

doi:10.1002/ange.201104342

Cited by 42 publications

(80 citation statements)

References 41 publications

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“…[2,3] It was demonstrated in a P. aeruginosa model of infection that the lectin is involved in lung injury and mortality [4][5][6][7] and recent data suggested that LecA promotes bacterial invasion into host cells. [9,15] These studies clearly highlighted the potential benefit of oligovalent interactions since dissociation constants lower than 90 nm and 20 nm were obtained for tetravalent [11,16] and divalent [13] compounds, respectively. 30 .…”

mentioning

confidence: 79%

“…In both structures, the asymmetric unit containing one LecA tetramer provided clear density, however, better ligand density was observed for the cocrystalisation using Li 2 SO 4 . [9,14] The triazole ring was also clearly seen and was stabilized by a water-bridged interaction involving the side chains of His50, Tyr36 and Asp47. [9,14] The triazole ring was also clearly seen and was stabilized by a water-bridged interaction involving the side chains of His50, Tyr36 and Asp47.…”

Section: Methodsmentioning

confidence: 99%

“…[1] In the case of P. aeruginosa, the structural basis for the preference of the LecA lectin towards galactose and globotriaosylceramide (Gb3) was elucidated. This structural knowledge has stimulated intense work to design templates presenting galactose residues with a spacing that matches the dimeric geometry of LecA neighboring binding sites [8][9][10][11][12][13][14][15][16] with the potential of acting as anti-pathogenic agents [17,18] or disrupting biofilm formation. [7] The lectin is a tetramer and structural data demonstrated an overall rectangular shape with pairing of neighboring binding sites separated by ca.…”

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confidence: 99%

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A LecA Ligand Identified from a Galactoside‐Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa

et al. 2014

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Lectin LecA is a virulence factor of Pseudomonas aeruginosa involved in lung injury, mortality, and cellular invasion. Ligands competing with human glycoconjugates for LecA binding are thus promising candidates to counteract P. aeruginosa infections. We have identified a novel divalent ligand from a focused galactoside(Gal)-conjugate array which binds to LecA with very high affinity (Kd = 82 nM). Crystal structures of LecA complexed with the ligand together with modeling studies confirmed its ability to chelate two binding sites of LecA. The ligand lowers cellular invasiveness of P. aeruginosa up to 90 % when applied in the range of 0.05-5 μM. Hence, this ligand might lead to the development of drugs against P. aeruginosa infection.

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confidence: 79%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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A LecA Ligand Identified from a Galactoside‐Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa

et al. 2014

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“…13,[32][33][34][35][36][37][38] Nevertheless, the topology brings an additional benefit allowing high binding with only trivalent clusters.…”

Section: Synthesis Of Glycocluster Oligonucleotide Conjugatesmentioning

confidence: 98%

Importance of topology for glycocluster binding to Pseudomonas aeruginosa and Burkholderia ambifaria bacterial lectins

et al. 2015

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Pseudomonas aeruginosa (PA) and Burkholderia ambifaria (BA) are two opportunistic Gram negative bacteria and major infectious agents involved in lung infection of cystic fibrosis patients. Both bacteria can develop resistance to conventional antibiotherapies. An alternative strategy consists of targeting virulence factors in particular lectins with high affinity ligands such as multivalent glycoclusters. LecA (PA-IL) and LecB (PA-IIL) are two tetravalent lectins from PA that recognise galactose and fucose respectively. BambL lectin from BA is trimeric with 2 binding sites per monomer and is also specific for fucose. These three lectins are potential therapeutic targets in an anti-adhesive anti-bacterial approach. Herein, we report the synthesis of 18 oligonucleotide pentofuranose-centered or mannitol-centered glycoclusters leading to tri-, penta- or decavalent clusters with different topologies. The linker arm length between the core and the carbohydrate epitope was also varied leading to 9 galactoclusters targeting LecA and 9 fucoclusters targeting both LecB and BambL. Their dissociation constants (Kd) were determined using a DNA-based carbohydrate microarray technology. The trivalent xylo-centered galactocluster and the ribo-centered fucocluster exhibited the best affinity for LecA and LecB respectively while the mannitol-centered decafucocluster displayed the best affinity to BambL. These data demonstrated that the topology and nature of linkers were the predominant factors for achieving high affinity rather than valency.

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“…Because methyl‐α‐ d ‐galactoside (αMeGal) has shown a protective effect against P. aeruginosa infections in a mice model, glycocompounds targeting LecA are highly sought after and in the recent years, emphasis has been placed on the synthesis of multivalent ones in particularly since some display potential in biofilm inhibition . Here we described the structure of LecA in complex with melibiose at 1.75 angstrom resolution where in addition to the galactose binding site, a secondary binding site has been identified.…”

Section: Introductionmentioning

confidence: 99%

Secondary sugar binding site identified for LecA lectin from Pseudomonas aeruginosa

2013

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The galactose-specific lectin LecA from Pseudomonas aeruginosa is a target for the development of new anti-infectious compounds. Sugar based molecules with anti-adhesive properties present great potential in the fight against bacterial infection and biofilm formation. LecA is specific for oligosaccharides with terminal α-galactoside residues and displays strong affinity for melibiose (αGal1-6Glc) with a Kd of 38.8 µM. The crystal structure of LecA/melibiose complex shows classical calcium-bridged binding of αGal in the primary binding site but also revealed a secondary sugar binding site with glucose bound. This sugar binding site is in close proximity to the galactose binding one, is independent of calcium and mainly involves interactions with a symmetry-related protein. This discovery would help to the design of new potent inhibitors targeting both binding sites.

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A Glycopeptide Dendrimer Inhibitor of the Galactose‐Specific Lectin LecA and of Pseudomonas aeruginosa Biofilms

Cited by 42 publications

References 41 publications

A LecA Ligand Identified from a Galactoside‐Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa

A LecA Ligand Identified from a Galactoside‐Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa

Importance of topology for glycocluster binding to Pseudomonas aeruginosa and Burkholderia ambifaria bacterial lectins

Secondary sugar binding site identified for LecA lectin from Pseudomonas aeruginosa

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