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

doi:10.1021/acs.jmedchem.9b00481

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 journal › Article › peer-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 language	English
Pages (from-to)	7722-7738
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00481
Publication status	Published - 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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Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa BiofilmsAccepted author manuscript, 1.52 MB

Cite this

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, 62(17), 7722-7738. https://doi.org/10.1021/acs.jmedchem.9b00481

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title = "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.",

keywords = "structural basis, nitric oxide, lectin lecb, iron uptake, siderophore, tobramycin, binding, recognition, biosynthesis, pathogenesis",

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

note = "{\textcopyright} 2018 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher{\textquoteright}s self-archiving policy. Further copying may not be permitted; contact the publisher for details.",

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month = aug,

day = "26",

doi = "10.1021/acs.jmedchem.9b00481",

language = "English",

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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

TY - JOUR

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.

AB - 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.

KW - structural basis

KW - nitric oxide

KW - lectin lecb

KW - iron uptake

KW - siderophore

KW - tobramycin

KW - binding

KW - recognition

KW - biosynthesis

KW - pathogenesis

UR - http://www.scopus.com/inward/record.url?scp=85072134406&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.9b00481

DO - 10.1021/acs.jmedchem.9b00481

M3 - Article

SN - 0022-2623

VL - 62

SP - 7722

EP - 7738

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 17

ER -

Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms

Abstract

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Keywords

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Peter Cragg

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Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms

Abstract

Bibliographical note

Keywords

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Peter Cragg

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