Structural Considerations for Building Synthetic Glycoconjugates as Inhibitors for Pseudomonas aeruginosa Lectins

Abstract

Pseudomonas aeruginosa is a pathogenic bacterium, responsible for a large portion of nosocomial infections globally and designated as critical priority by the World Health Organisation. Its characteristic carbohydrate‐binding proteins LecA and LecB, which play a role in biofilm‐formation and lung‐infection, can be targeted by glycoconjugates. Here we review the wide range of inhibitors for these proteins (136 references), highlighting structural features and which impact binding affinity and/or therapeutic effects, including carbohydrate selection; linker length and rigidity; and scaffold topology, particularly for multivalent candidates. We also discuss emerging therapeutic strategies, which build on targeting of LecA and LecB, such as anti‐biofilm activity, anti‐adhesion and drug‐delivery, with promising prospects for medicinal chemistry.

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

“…[4] PA LecA is demonstrated to be crucial for biofilm formation and internalization, while the extracellular LecB plays a key role in bacterial adhesion to the host and biofilm formation. [5][6][7][8] Building synthetic glycoconjugates for the inhibition and modulation of bacterial lectins responsive for biofilm formation have shown promising results. [9,10] Unlike antibiotics, lectin inhibitors could prevent pathogenicity by interfering with virulence factors instead of killing the bacteria.…”

Switch-on luminescent sensing of unlabelled bacterial lectin by terbium(iii) glycoconjugate systems

“…Recently, we reviewed ligand design strategies for inhibition of PA's lectins, in hopes of finding non-bactericidal antiadhesion therapies for PA infections that would not add to the problem of antibiotic resistance. 19 Among the vast range of structures reported for targeting galactophilic LecA, with up to nanomolar affinities, are calixarenes, glycopeptide dendrimers, and carbohydrate-centred clusters as well as covalently-binding imaging agents. 11,20,21 Several of these also demonstrate biofilm-inhibition activity.…”

“…Shared characteristics among the most potent examples are: multivalency to exploit the glycocluster effect, galactoside epitopes functionalised at the anomeric position, and long, flexible linkers to a scaffold that allows bridging between the two vicinal binding sites on the lectin tetramer and/or chelation between different tetramers. 19 Metal complexes are poorly represented as inhibitors for PA lectins, despite the potential for new modes of action and properties like luminescence and magnetism. These could be advantageous for sensing, combined with high affinity.…”

“…Shared characteristics among the most potent examples are: multivalency to exploit the glycocluster effect, galactoside epitopes functionalised at the anomeric position, and long, flexible linkers to a scaffold that allows bridging between the two vicinal binding sites on the lectin tetramer and/or chelation between different tetramers. 19…”

“…We previously showed how the presence of a flexible linker impacts ability of metal complexes to interact with PA lectins, 22 and optimisation of linker arms to facilitate chelate binding of neighbouring carbohydrate-recognition domains has played an important role in developing high-affinity ligands for these lectins. 19,37,38…”