Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms

Marwa Taouai, Khouloud Chakroun, Roman Somer, Gaelle Michaud, David Giacalone, Mohamed Ben Maaouia, Auralie Vallin-Butruille, David Mathiron, Rym Abidi, Tamis Darbre, Peter Cragg, Catherine Mullie, Jean-Louis Reymond, George O'Toole, Mohammed Benazza

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish
    Pages (from-to)7722-7738
    Number of pages17
    JournalJournal of Medicinal Chemistry
    Volume62
    Issue number17
    DOIs
    Publication statusPublished - 26 Aug 2019

    Bibliographical note

    © 2018 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

    Keywords

    • structural basis
    • nitric oxide
    • lectin lecb
    • iron uptake
    • siderophore
    • tobramycin
    • binding
    • recognition
    • biosynthesis
    • pathogenesis

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