Pillar[5]arene-Based Polycationic Glyco[2]rotaxanes Designed as Pseudomonas aeruginosa Antibiofilm Agents

Abstract

Pseudomonas aeruginosa is a human pathogen belonging to the top priorities for the discovery of new therapeutic solutions. Its propensity to generate biofilms strongly complicates the treatments required to cure P. aeruginosa infections. Herein we describe the synthesis of a series of novel rotaxanes comprised of a central galactosylated pillar [5]arene, a tetrafucosylated dendron and a tetra-guanidinium subunit. Strategically, we exploited a supramolecular assembly technology to generate complex rotaxanes from relatively simple subcomponents. The final glycorotaxanes displayed high affinity for the two P. aeruginosa lectins LecA and LecB as evaluated by Isothermal Titration Calorimetry. Potent inhibition levels of P. aeruginosa biofilm growth were evidenced showing that the three subunits of the glycorotaxanes work synergistically. Such antibiofilm potency had rarely been reached in the literature. Importantly, none of the final rotaxanes was bactericidal, showing that their antibiofilm activity is lectinmediated but does not depend on bacteria killing, which is a rare feature for antibiofilm agents.

Novel Approaches To Design Glycan‐Based Antibacterial Inhibitors

“…To generate a potent biofilm inhibitor targeting the P. aeruginosa lectins LecA and LecB, Mohy El Dine et al chose a supramolecular scaffold, and combined a cationic unit that showed promising anti-biofilm properties, but lacked selectivity for the target lectin, with heteroglycoclusters to selectively target LecA and LecB (Figure 2C). [22] The heterovalent glyco[2]rotaxanes 10 a-c were generated by supramolecular assembly of the central pillar[5]arene 7 deca-galactosylated with 9 to address LecA, the tetrafucosylated dendron 6 to target LecB, and the polyguanidinium tail 8 as cationic unit to prevent biofilm formation. Binding assays were performed, and valency-corrected RIP values were obtained, which were related to the references β-d-GalOMe (LecA) and α-l-FucOMe (LecB) (Table 2).…”

Copillar[5]arene Chemistry: Synthesis and Applications

“…112 Such advanced copillararenes are now being assayed for diverse biological applications including bacterial biofilm eradication. 123 They are also being studied for applications in antivirulence, [124][125][126] as antibiofilm agents and for multivalent enzyme inhibition.…”

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

“…This comprehensive overview will be of value to a broad audience of synthetic and medicinal chemists in academia and in industry, aiming to build new therapeutic or diagnostic tools against PA. This topic is timely, and indeed some inspiring examples have been published in the last two years illustrating novel complementary therapeutic approaches, including targeted biofilm inhibition activity, [11] directing antibiotics to the bacteria by lectintargeting, [12] and hijacking the ability of the bacterium to utilise glycocluster-conjugated siderophores for iron-transport as a 'Trojan horse' strategy. [13] 1.1.…”