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/anie.201104342

Cited by 156 publications

(212 citation statements)

References 41 publications

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“…The same trend was observed by Pieters who showed that digalactosides differing from only four methylenes displayed a difference of K d values of almost four-times (28 vs. 130 nM). 27 The best galactoclusters reported in the literature 34 20 and 176 nM 11 for tetragalactosides. The galactoclusters 1 and 2 with the K d values of 194 nM and 157 nM respectively are in the same range.…”

Section: Resultsmentioning

confidence: 99%

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Mannose-centered aromatic galactoclusters inhibit the biofilm formation of Pseudomonas aeruginosa

et al. 2015

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Pseudomonas aeruginosa (PA) is a major public health care issue due to its ability to develop antibiotic resistance mainly through adhesion and biofilm formation. Therefore, targeting the bacterial molecular arsenal involved in its adhesion and the formation of its biofilm appears as a promising tool against this pathogen. The galactose-binding LecA (or PA-IL) has been described as one of the PA virulence factors involved in these processes. Herein, the affinity of three tetravalent mannose-centered galactoclusters toward LecA was evaluated with five different bioanalytical methods: HIA, ELLA, SPR, ITC and DNA-based glycoarray. Inhibitory potential towards biofilms was then assessed for the two glycoclusters with highest affinity towards LecA (Kd values of 157 and 194 nM from ITC measurements). An inhibition of biofilm formation of 40% was found for these galactoclusters at 10 μM concentration. Applications of these macromolecules in anti-bacterial therapy are therefore possible through an anti-adhesive strategy.

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Section: Resultsmentioning

confidence: 99%

“…16 Inhibition of LecA with synthetic ligands can be achieved with high affinity oligogalactosylated ligands. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] High binding can be obtained thanks to the so called glycoside cluster effect. 32,33 The design of multivalent ligands targeting LecA has been recently reviewed.…”

Section: Introductionmentioning

confidence: 99%

Mannose-centered aromatic galactoclusters inhibit the biofilm formation of Pseudomonas aeruginosa

et al. 2015

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“…21 In these structures the terminal glycosidic group was observed to bind at the expected position. In the case of the LecB complex with 2G0 and the LecA complex with GalBG0 the tripeptide portion of the ligands was disordered.…”

Section: Structural Studiesmentioning

confidence: 91%

“…1). 20,21 Structure-activity relationship studies show that multivalency is crucial for biofilm inhibition and dispersal with these ligands.…”

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confidence: 99%

Glycopeptide dendrimers as Pseudomonas aeruginosa biofilm inhibitors

2013

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Synthetic glycopeptide dendrimers composed of a branched oligopeptide tree structure appended with glycosidic groups at its multiple N-termini were investigated for binding to the Pseudomonas aeruginosa lectins LecB and LecA. These lectins are partly responsible for the formation of antibiotic resistant biofilms in the human pathogenic bacterium P. aeruginosa, which causes lethal airway infections in immune-compromised and cystic fibrosis patients. Glycopeptide dendrimers with high affinity to the lectins were identified by screening of combinatorial libraries. Several of these dendrimers, in particular the LecB specific glycopeptide dendrimers FD2 and D-FD2 and the LecA specific glycopeptide dendrimers GalAG2 and GalBG2, also efficiently block P. aeruginosa biofilm formation and induce biofilm dispersal in vitro. Structure-activity relationship and structural studies are reviewed, in particular the observation that multivalency is essential to the anti-biofilm effect in these dendrimers.

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“…24, 25). [61][62][63] Pieters et al reported bivalent galactosides which are thought to bind simultaneously to two of the four carbohydrate binding sites of LecA as concluded from the high potency (IC 50 = 220 nM). [64] LecB displays an unusually strong affinity for α-fucosides in the high nanomolar range, which could be explained by the crystal structure of the complex: [65] the presence of two calcium ions in the binding site and an additional lipophilic contact of the methyl group contribute to the strong binding.…”

Section: Ta Rgeting Quorum Sensingmentioning

confidence: 99%

New Approaches to Control Infections: Anti-biofilm Strategies against Gram-negative Bacteria

Sommer

Joachim²,

Wagner³

et al. 2013

Chimia

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Hospital-acquired bacterial infections, especially with Gram-negative pathogens, present a major threat due to the rapid spread of antibiotic-resistant strains. Targeting mechanisms of bacterial virulence has recently appeared as a promising new therapeutic paradigm. Biofilm formation is a bacterial lifestyle, which offers a survival advantage through its protective matrix against host immune defense and antibiotic treatment. Interfering with biogenesis of adhesive organelles, bacterial communication or carbohydrate-mediated adhesion as anti-biofilm strategies are reviewed.

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

Cited by 156 publications

References 41 publications

Mannose-centered aromatic galactoclusters inhibit the biofilm formation of Pseudomonas aeruginosa

Mannose-centered aromatic galactoclusters inhibit the biofilm formation of Pseudomonas aeruginosa

Glycopeptide dendrimers as Pseudomonas aeruginosa biofilm inhibitors

New Approaches to Control Infections: Anti-biofilm Strategies against Gram-negative Bacteria

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