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 journalArticleResearchpeer-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

Fingerprint

Biofilms
Pseudomonas aeruginosa
Iron
Acids
Lectins
Hydroxamic Acids
Siderophores
Fucose
Flagella
Polysaccharides
Immune System
Bacteria
Pharmaceutical Preparations

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

Cite this

Taouai, M., Chakroun, K., Somer, R., Michaud, G., Giacalone, D., Ben Maaouia, M., ... Benazza, M. (2019). Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms. Journal of Medicinal Chemistry, 62(17), 7722-7738. https://doi.org/10.1021/acs.jmedchem.9b00481
Taouai, Marwa ; Chakroun, Khouloud ; Somer, Roman ; Michaud, Gaelle ; Giacalone, David ; Ben Maaouia, Mohamed ; Vallin-Butruille, Auralie ; Mathiron, David ; Abidi, Rym ; Darbre, Tamis ; Cragg, Peter ; Mullie, Catherine ; Reymond, Jean-Louis ; O'Toole, George ; Benazza, Mohammed . / Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 17. pp. 7722-7738.
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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.",
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Taouai, M, Chakroun, K, Somer, R, Michaud, G, Giacalone, D, Ben Maaouia, M, Vallin-Butruille, A, Mathiron, D, Abidi, R, Darbre, T, Cragg, P, Mullie, C, Reymond, J-L, O'Toole, G & Benazza, M 2019, 'Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms', Journal of Medicinal Chemistry, vol. 62, no. 17, pp. 7722-7738. https://doi.org/10.1021/acs.jmedchem.9b00481

Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms. / Taouai, Marwa ; Chakroun, Khouloud ; Somer, Roman; Michaud, Gaelle; Giacalone, David; Ben Maaouia, Mohamed; Vallin-Butruille, Auralie; Mathiron, David ; Abidi, Rym ; Darbre, Tamis; Cragg, Peter; Mullie, Catherine ; Reymond, Jean-Louis; O'Toole, George; Benazza, Mohammed .

In: Journal of Medicinal Chemistry, Vol. 62, No. 17, 26.08.2019, p. 7722-7738.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms

AU - Taouai, Marwa

AU - Chakroun, Khouloud

AU - Somer, Roman

AU - Michaud, Gaelle

AU - Giacalone, David

AU - Ben Maaouia, Mohamed

AU - Vallin-Butruille, Auralie

AU - Mathiron, David

AU - Abidi, Rym

AU - Darbre, Tamis

AU - Cragg, Peter

AU - Mullie, Catherine

AU - Reymond, Jean-Louis

AU - O'Toole, George

AU - Benazza, Mohammed

N1 - © 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.

PY - 2019/8/26

Y1 - 2019/8/26

N2 - 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.

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KW - structural basis

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KW - iron uptake

KW - siderophore

KW - tobramycin

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