Intrinsic antibacterial activity of nanoparticles made of β-cyclodextrins potentiates their effect as drug nanocarriers against tuberculosis

Arnaud Machelart; Giuseppina Salzano; Xue Li; Aurore Demars; Anne Sophie Debrie; Mario Menendez-Miranda; Elisabetta Pancani; Samuel Jouny; Eik Hoffmann; Nathalie Deboosere; Imène Belhaouane; Carine Rouanet; Sophie Simar; Smaïl Talahari; Valerie Giannini; Baptiste Villemagne; Marion Flipo; Roland Brosch; Fabrice Nesslany; Benoit Deprez; Eric Muraille; Camille Locht; Alain R. Baulard; Nicolas Willand; Laleh Majlessi; Ruxandra Gref; Priscille Brodin

doi:10.1021/acsnano.8b07902

Intrinsic antibacterial activity of nanoparticles made of β-cyclodextrins potentiates their effect as drug nanocarriers against tuberculosis

Arnaud Machelart
, Giuseppina Salzano
, Xue Li
, Aurore Demars
, Anne Sophie Debrie
, Mario Menendez-Miranda
, Elisabetta Pancani
, Samuel Jouny
, Eik Hoffmann
, Nathalie Deboosere
, Imène Belhaouane
, Carine Rouanet
, Sophie Simar
, Smaïl Talahari
, Valerie Giannini
, Baptiste Villemagne
, Marion Flipo
, Roland Brosch
, Fabrice Nesslany
, Benoit Deprez

Eric Muraille, Camille Locht, Alain R. Baulard, Nicolas Willand, Laleh Majlessi, Ruxandra Gref, Priscille Brodin

Research Unit in Biology of Microorganisms

Research output: Contribution to journal › Article › peer-review

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Abstract

Multi-drug-resistant tuberculosis (TB) is a major public health problem, concerning about half a million cases each year. Patients hardly adhere to the current strict treatment consisting of more than 10,000 tablets over a 2-year period. There is a clear need for efficient and better formulated medications. We have previously shown that nanoparticles made of cross-linked poly-β-cyclodextrins (pβCD) are efficient vehicles for pulmonary delivery of powerful combinations of anti-TB drugs. Here, we report that in addition to being efficient drug carriers, pβCD nanoparticles are endowed with intrinsic antibacterial properties. Empty pβCD nanoparticles are able to impair Mycobacterium tuberculosis (Mtb) establishment after pulmonary administration in mice. pβCD hamper colonization of macrophages by Mtb by interfering with lipid rafts, without inducing toxicity. Moreover, pβCD provoke macrophage apoptosis, leading to depletion of infected cells, thus creating a lung microenvironment detrimental to Mtb persistence. Taken together, our results suggest that pβCD nanoparticles loaded or not with antibiotics have an antibacterial action on their own and could be used as a carrier in drug regimen formulations effective against TB.

Original language	English
Pages (from-to)	3992-4007
Number of pages	16
Journal	ACS nano
Volume	13
Issue number	4
DOIs	https://doi.org/10.1021/acsnano.8b07902
Publication status	Published - 23 Apr 2019

Funding

We gratefully acknowledge F. Leroux, H. Bauderlique, O. R. Song, I. Ricard, and A. Vandeputte for technical assistance and helpful discussions. We also acknowledge R. Prath, N. Vandenabeele, and D. Legrand for technical assistance in BSL3 and animal facilities. We are grateful to Roquette for kindly providing us with a sample of β-cyclodextrin. We acknowledge the PICT-IBiSA and F. Lafont from BiCEL for providing access to microscopy equipment. Financial support for this work was provided by the European Community (CycloNHit no. 608407, ERC-STG INTRACELLTB no. 260901, MM4TB no. 260872), the Agence Nationale de la Recherche (ANR-10-EQPX-04-01, ANR-14-CE08-0017, ANR-16-CE35-0009), the Projet Transversal de l’Institut Pasteur (PTR441, PTR22-16), the EMBO Young Investigator Program, the Feder (12001407 (D-AL) Equipex Imaginex BioMed), the Reǵ ion Hauts-de-France (convention no. 12000080), and the Fondation pour la Recherche Medicale (SPF20170938709). This work was supported by a public grant overseen by the French National Research Agency (ANR) as part of the “Investissements d’Avenir” program (Labex NanoSaclay, ANR-10-LABX-0035).

Funders	Funder number
Equipex Imaginex BioMed
European Molecular Biology Organization
Agence Nationale de la Recherche	ANR-16-CE35-0009, ANR-14-CE08-0017, ANR-10-EQPX-04-01
Projet Transversal de l’Institut Pasteur	PTR441, PTR22-16
Seventh Framework Programme	260872, 260901
Reǵ ion Hauts-de-France	12000080
European Commission	608407
Fondation pour la Recherche Médicale	SPF20170938709
Labex NanoSaclay	ANR-10-LABX-0035
European Regional Development Fund	12001407

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

antibacterial activity
cyclodextrins
drug nanocarrier
host-directed therapy
tuberculosis

Access to Document

10.1021/acsnano.8b07902

acs.jpcc.9b05921Final published version, 11.8 MBLicence: CC BY

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Machelart, A., Salzano, G., Li, X., Demars, A., Debrie, A. S., Menendez-Miranda, M., Pancani, E., Jouny, S., Hoffmann, E., Deboosere, N., Belhaouane, I., Rouanet, C., Simar, S., Talahari, S., Giannini, V., Villemagne, B., Flipo, M., Brosch, R., Nesslany, F., ... Brodin, P. (2019). Intrinsic antibacterial activity of nanoparticles made of β-cyclodextrins potentiates their effect as drug nanocarriers against tuberculosis. ACS nano, 13(4), 3992-4007. https://doi.org/10.1021/acsnano.8b07902

@article{e6147131e7c2455aac08c832d40273db,

title = "Intrinsic antibacterial activity of nanoparticles made of β-cyclodextrins potentiates their effect as drug nanocarriers against tuberculosis",

abstract = "Multi-drug-resistant tuberculosis (TB) is a major public health problem, concerning about half a million cases each year. Patients hardly adhere to the current strict treatment consisting of more than 10,000 tablets over a 2-year period. There is a clear need for efficient and better formulated medications. We have previously shown that nanoparticles made of cross-linked poly-β-cyclodextrins (pβCD) are efficient vehicles for pulmonary delivery of powerful combinations of anti-TB drugs. Here, we report that in addition to being efficient drug carriers, pβCD nanoparticles are endowed with intrinsic antibacterial properties. Empty pβCD nanoparticles are able to impair Mycobacterium tuberculosis (Mtb) establishment after pulmonary administration in mice. pβCD hamper colonization of macrophages by Mtb by interfering with lipid rafts, without inducing toxicity. Moreover, pβCD provoke macrophage apoptosis, leading to depletion of infected cells, thus creating a lung microenvironment detrimental to Mtb persistence. Taken together, our results suggest that pβCD nanoparticles loaded or not with antibiotics have an antibacterial action on their own and could be used as a carrier in drug regimen formulations effective against TB.",

keywords = "antibacterial activity, cyclodextrins, drug nanocarrier, host-directed therapy, tuberculosis",

author = "Arnaud Machelart and Giuseppina Salzano and Xue Li and Aurore Demars and Debrie, \{Anne Sophie\} and Mario Menendez-Miranda and Elisabetta Pancani and Samuel Jouny and Eik Hoffmann and Nathalie Deboosere and Im{\`e}ne Belhaouane and Carine Rouanet and Sophie Simar and Sma{\"i}l Talahari and Valerie Giannini and Baptiste Villemagne and Marion Flipo and Roland Brosch and Fabrice Nesslany and Benoit Deprez and Eric Muraille and Camille Locht and Baulard, \{Alain R.\} and Nicolas Willand and Laleh Majlessi and Ruxandra Gref and Priscille Brodin",

note = "Funding Information: We gratefully acknowledge F. Leroux, H. Bauderlique, O. R. Song, I. Ricard, and A. Vandeputte for technical assistance and helpful discussions. We also acknowledge R. Prath, N. Vandenabeele, and D. Legrand for technical assistance in BSL3 and animal facilities. We are grateful to Roquette for kindly providing us with a sample of β-cyclodextrin. We acknowledge the PICT-IBiSA and F. Lafont from BiCEL for providing access to microscopy equipment. Financial support for this work was provided by the European Community (CycloNHit no. 608407, ERC-STG INTRACELLTB no. 260901, MM4TB no. 260872), the Agence Nationale de la Recherche (ANR-10-EQPX-04-01, ANR-14-CE08-0017, ANR-16-CE35-0009), the Projet Transversal de l{\textquoteright}Institut Pasteur (PTR441, PTR22-16), the EMBO Young Investigator Program, the Feder (12001407 (D-AL) Equipex Imaginex BioMed), the Reǵ ion Hauts-de-France (convention no. 12000080), and the Fondation pour la Recherche Medicale (SPF20170938709). This work was supported by a public grant overseen by the French National Research Agency (ANR) as part of the “Investissements d{\textquoteright}Avenir” program (Labex NanoSaclay, ANR-10-LABX-0035). Publisher Copyright: {\textcopyright} 2019 American Chemical Society. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = apr,

day = "23",

doi = "10.1021/acsnano.8b07902",

language = "English",

volume = "13",

pages = "3992--4007",

journal = "ACS nano",

issn = "1936-0851",

publisher = "American Chemical Society",

number = "4",

}

Machelart, A, Salzano, G, Li, X, Demars, A, Debrie, AS, Menendez-Miranda, M, Pancani, E, Jouny, S, Hoffmann, E, Deboosere, N, Belhaouane, I, Rouanet, C, Simar, S, Talahari, S, Giannini, V, Villemagne, B, Flipo, M, Brosch, R, Nesslany, F, Deprez, B, Muraille, E, Locht, C, Baulard, AR, Willand, N, Majlessi, L, Gref, R & Brodin, P 2019, 'Intrinsic antibacterial activity of nanoparticles made of β-cyclodextrins potentiates their effect as drug nanocarriers against tuberculosis', ACS nano, vol. 13, no. 4, pp. 3992-4007. https://doi.org/10.1021/acsnano.8b07902

TY - JOUR

T1 - Intrinsic antibacterial activity of nanoparticles made of β-cyclodextrins potentiates their effect as drug nanocarriers against tuberculosis

AU - Machelart, Arnaud

AU - Salzano, Giuseppina

AU - Li, Xue

AU - Demars, Aurore

AU - Debrie, Anne Sophie

AU - Menendez-Miranda, Mario

AU - Pancani, Elisabetta

AU - Jouny, Samuel

AU - Hoffmann, Eik

AU - Deboosere, Nathalie

AU - Belhaouane, Imène

AU - Rouanet, Carine

AU - Simar, Sophie

AU - Talahari, Smaïl

AU - Giannini, Valerie

AU - Villemagne, Baptiste

AU - Flipo, Marion

AU - Brosch, Roland

AU - Nesslany, Fabrice

AU - Deprez, Benoit

AU - Muraille, Eric

AU - Locht, Camille

AU - Baulard, Alain R.

AU - Willand, Nicolas

AU - Majlessi, Laleh

AU - Gref, Ruxandra

AU - Brodin, Priscille

N1 - Funding Information: We gratefully acknowledge F. Leroux, H. Bauderlique, O. R. Song, I. Ricard, and A. Vandeputte for technical assistance and helpful discussions. We also acknowledge R. Prath, N. Vandenabeele, and D. Legrand for technical assistance in BSL3 and animal facilities. We are grateful to Roquette for kindly providing us with a sample of β-cyclodextrin. We acknowledge the PICT-IBiSA and F. Lafont from BiCEL for providing access to microscopy equipment. Financial support for this work was provided by the European Community (CycloNHit no. 608407, ERC-STG INTRACELLTB no. 260901, MM4TB no. 260872), the Agence Nationale de la Recherche (ANR-10-EQPX-04-01, ANR-14-CE08-0017, ANR-16-CE35-0009), the Projet Transversal de l’Institut Pasteur (PTR441, PTR22-16), the EMBO Young Investigator Program, the Feder (12001407 (D-AL) Equipex Imaginex BioMed), the Reǵ ion Hauts-de-France (convention no. 12000080), and the Fondation pour la Recherche Medicale (SPF20170938709). This work was supported by a public grant overseen by the French National Research Agency (ANR) as part of the “Investissements d’Avenir” program (Labex NanoSaclay, ANR-10-LABX-0035). Publisher Copyright: © 2019 American Chemical Society. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/4/23

Y1 - 2019/4/23

N2 - Multi-drug-resistant tuberculosis (TB) is a major public health problem, concerning about half a million cases each year. Patients hardly adhere to the current strict treatment consisting of more than 10,000 tablets over a 2-year period. There is a clear need for efficient and better formulated medications. We have previously shown that nanoparticles made of cross-linked poly-β-cyclodextrins (pβCD) are efficient vehicles for pulmonary delivery of powerful combinations of anti-TB drugs. Here, we report that in addition to being efficient drug carriers, pβCD nanoparticles are endowed with intrinsic antibacterial properties. Empty pβCD nanoparticles are able to impair Mycobacterium tuberculosis (Mtb) establishment after pulmonary administration in mice. pβCD hamper colonization of macrophages by Mtb by interfering with lipid rafts, without inducing toxicity. Moreover, pβCD provoke macrophage apoptosis, leading to depletion of infected cells, thus creating a lung microenvironment detrimental to Mtb persistence. Taken together, our results suggest that pβCD nanoparticles loaded or not with antibiotics have an antibacterial action on their own and could be used as a carrier in drug regimen formulations effective against TB.

AB - Multi-drug-resistant tuberculosis (TB) is a major public health problem, concerning about half a million cases each year. Patients hardly adhere to the current strict treatment consisting of more than 10,000 tablets over a 2-year period. There is a clear need for efficient and better formulated medications. We have previously shown that nanoparticles made of cross-linked poly-β-cyclodextrins (pβCD) are efficient vehicles for pulmonary delivery of powerful combinations of anti-TB drugs. Here, we report that in addition to being efficient drug carriers, pβCD nanoparticles are endowed with intrinsic antibacterial properties. Empty pβCD nanoparticles are able to impair Mycobacterium tuberculosis (Mtb) establishment after pulmonary administration in mice. pβCD hamper colonization of macrophages by Mtb by interfering with lipid rafts, without inducing toxicity. Moreover, pβCD provoke macrophage apoptosis, leading to depletion of infected cells, thus creating a lung microenvironment detrimental to Mtb persistence. Taken together, our results suggest that pβCD nanoparticles loaded or not with antibiotics have an antibacterial action on their own and could be used as a carrier in drug regimen formulations effective against TB.

KW - antibacterial activity

KW - cyclodextrins

KW - drug nanocarrier

KW - host-directed therapy

KW - tuberculosis

UR - https://www.scopus.com/pages/publications/85062868728

U2 - 10.1021/acsnano.8b07902

DO - 10.1021/acsnano.8b07902

M3 - Article

C2 - 30822386

AN - SCOPUS:85062868728

SN - 1936-0851

VL - 13

SP - 3992

EP - 4007

JO - ACS nano

JF - ACS nano

IS - 4

ER -

Intrinsic antibacterial activity of nanoparticles made of β-cyclodextrins potentiates their effect as drug nanocarriers against tuberculosis

Abstract

Funding

UN SDGs

Keywords

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