Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms

Opportunistic Gram-negative Pseudomonas aeruginosa uses adhesins (e.g., LecA
and LecB lectins, type VI pili and flagella)
and iron to invade host cells with the formation of a biofilm, a thick
barrier that protects bacteria from drugs and host immune system.
Hindering iron uptake and disrupting adhesins’ function could
be a relevant antipseudomonal strategy. To test this hypothesis, we
designed an iron-chelating glycocluster incorporating a tetrahydroxamic
acid and α-l-fucose bearing linker to interfere with
both iron uptake and the glycan recognition process involving the
LecB lectin. Iron depletion led to increased production of the siderophore
pyoverdine by P. aeruginosa to counteract
the loss of iron uptake, and strong biofilm inhibition was observed
not only with the α-l-fucocluster (72%), but also with
its α-d-manno (84%), and α-d-gluco (92%) counterparts used as negative
controls. This unprecedented finding suggests that both LecB and biofilm
inhibition are closely related to the presence of hydroxamic acid
groups.