Modified Galacto‐ or Fuco‐Clusters Exploiting the Siderophore Pathway to Inhibit the LecA‐ or LecB‐Associated Virulence of Pseudomonas aeruginosa

Abstract

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.

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

“…As a result, numerous LasB inhibitors with a range of zinc binding moieties have been discovered (Galdino et al , 2019 ; Velázquez‐Libera et al , 2019 ; Leiris et al , 2021 ; Kaya et al , 2022 ). Other targeted virulence factors in P. aeruginosa include the lectins A and B responsible for the formation of biofilms which can be inhibited by carbohydrate derivatives (Sommer et al , 2019 ; Madaoui et al , 2020 ; Schütz et al , 2021 ), or the transcriptional regulator PqsR (Soheili et al , 2019 ). In S. aureus , the discovery of quorum‐quenching agents (Kuo et al , 2015 ) or adhesion inhibitors (Fernandes de Oliveira et al , 2021 ) gave promising hits.…”

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

“…Carbohydrate-centred clusters derived from MAN4 (Section 3.1) functionalised to include catechol or hydroxamate arms for iron-chelation were also studied with PAO1 (and several knockout strains), indicating that catechol-appended galactoclusers penetrated the bacterial envelope, exploiting the siderophore pathway in a "Trojan horse" strategy. [136] Despite evidence for localisation at the cell membrane (where 5 % of LecA is located), no decrease in virulence was observed. Protection assays of human pulmonary cell cultures against PA demonstrate up to 70 % protection with galactocluster-siderophore conjugates (e. g. MAN10), but disappointingly, this was similar to catechol-free analogues.…”

“…Carbohydrate‐centred clusters derived from MAN4 (Section 3.1) functionalised to include catechol or hydroxamate arms for iron‐chelation were also studied with PAO1 (and several knockout strains), indicating that catechol‐appended galactoclusers penetrated the bacterial envelope, exploiting the siderophore pathway in a “Trojan horse” strategy [136] . Despite evidence for localisation at the cell membrane (where 5 % of LecA is located), no decrease in virulence was observed.…”