Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms

Abstract

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.

Hydroxamate siderophores: Natural occurrence, chemical synthesis, iron binding affinity and use as Trojan horses against pathogens

“…As metal chelators, Desferal, the brand name of desferrioxamine B ( 6), was the first drug used for the treatment of metal poisoning, namely iron overloading [22,112]. Also, the hydroxamate groups have shown unprecedented activity against the growth of P. aeruginosa biofilms (which confer cells extra resistance to antibiotics by adhering in the form of a film) when they were combined with glycol motifs in a bifunctional molecule, in which the glycol targeted the adhesion of cells and hydroxamate deprived cells of iron [113].…”

Antimicrobial Activity of Calixarenes and Related Macrocycles

“…Benazza and colleagues prepared fuco-, 157; manno-, 158; and glucocluster, 159, cone-calix [4]arene derivatives, shown in Figures 23 and 24, and introduced an iron chelating hydroxamic acid region in each linker [76]. It was proposed that, in addition to binding to lectins, these compounds could sequester soluble iron, an essential nutrient for bacteria, to enhance their antibacterial activities.…”

“…A glycosylated calixarene binding to a lectin. Reprinted with permission from[76]. Copyright © 2019 American Chemical Society.…”

Multivalent and Multifunctional Calixarenes in Bionanotechnology

“…[67] Very recently, P. aeruginosa was selected by Benazza et al as target for calix [4]arenes functionalized at the lower rim with L-fucose or D-mannose units linked to the macrocycle through a spacer incorporating an hydroxamic acid moiety. [68] Beyond lectins, in fact, bacteria also exploit Fe 3+ cations to invade host cells and create the biofilm. The presence of hydroxamic acids, strong Fe 3+ chelators, can therefore hinder the metal uptake.…”