Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice

Nadine Hoffmann; Baoleri Lee; Morten Hentzer; Thomas Bovbjerg Rasmussen; Zhijun Song; Helle Krogh Johansen; Michael Givskov; Niels Høiby

doi:10.1128/AAC.01011-06

Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice

Nadine Hoffmann, Baoleri Lee, Morten Hentzer, Thomas Bovbjerg Rasmussen, Zhijun Song, Helle Krogh Johansen, Michael Givskov, Niels Høiby

209 Citations (Scopus)

Abstract

The consequences of O-acetylated alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected cystic fibrosis (CF) patients are tolerance to both antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials, azithromycin (AZM) has been shown to improve the lung function of CF patients. The present study was conducted in accordance with previous in vitro studies suggesting that the effect of AZM may be the inhibition of alginate production, blockage of quorum sensing (QS), and increased sensitivity to hydrogen peroxide and the complement system. Moreover, we show that AZM may affect the polymerization of P. aeruginosa alginate by the incomplete precipitation of polymerized alginate and high levels of readily dialyzable uronic acids. In addition, we find that mucoid bacteria in the stationary growth phase became sensitive to AZM, whereas cells in the exponential phase did not. Interestingly, AZM-treated P. aeruginosa lasI mutants appeared to be particularly resistant to serum, whereas bacteria with a functional QS system did not. We show in a CF mouse model of chronic P. aeruginosa lung infection that AZM treatment results in the suppression of QS-regulated virulence factors, significantly improves the clearance of P. aeruginosa alginate biofilms, and reduces the severity of the lung pathology compared to that in control mice. We conclude that AZM attenuates the virulence of P. aeruginosa, impairs its ability to form fully polymerized alginate biofilms, and increases its sensitivity to complement and stationary-phase killing, which may explain the clinical efficacy of AZM.

Original language	English
Journal	Antimicrobial Agents and Chemotherapy
Volume	51
Issue number	10
Pages (from-to)	3677-87
Number of pages	10
ISSN	0066-4804
DOIs	https://doi.org/10.1128/AAC.01011-06
Publication status	Published - 2007
Externally published	Yes

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Hoffmann, N., Lee, B., Hentzer, M., Rasmussen, T. B., Song, Z., Johansen, H. K., Givskov, M., & Høiby, N. (2007). Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice. Antimicrobial Agents and Chemotherapy, 51(10), 3677-87. https://doi.org/10.1128/AAC.01011-06

Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice. / Hoffmann, Nadine; Lee, Baoleri; Hentzer, Morten et al.
In: Antimicrobial Agents and Chemotherapy, Vol. 51, No. 10, 2007, p. 3677-87.

Research output: Contribution to journal › Journal article › Research › peer-review

Hoffmann, N, Lee, B, Hentzer, M, Rasmussen, TB, Song, Z, Johansen, HK, Givskov, M & Høiby, N 2007, 'Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice', Antimicrobial Agents and Chemotherapy, vol. 51, no. 10, pp. 3677-87. https://doi.org/10.1128/AAC.01011-06

Hoffmann N, Lee B, Hentzer M, Rasmussen TB, Song Z, Johansen HK et al. Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice. Antimicrobial Agents and Chemotherapy. 2007;51(10):3677-87. doi: 10.1128/AAC.01011-06

Hoffmann, Nadine ; Lee, Baoleri ; Hentzer, Morten et al. / Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice. In: Antimicrobial Agents and Chemotherapy. 2007 ; Vol. 51, No. 10. pp. 3677-87.

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title = "Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice",

abstract = "The consequences of O-acetylated alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected cystic fibrosis (CF) patients are tolerance to both antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials, azithromycin (AZM) has been shown to improve the lung function of CF patients. The present study was conducted in accordance with previous in vitro studies suggesting that the effect of AZM may be the inhibition of alginate production, blockage of quorum sensing (QS), and increased sensitivity to hydrogen peroxide and the complement system. Moreover, we show that AZM may affect the polymerization of P. aeruginosa alginate by the incomplete precipitation of polymerized alginate and high levels of readily dialyzable uronic acids. In addition, we find that mucoid bacteria in the stationary growth phase became sensitive to AZM, whereas cells in the exponential phase did not. Interestingly, AZM-treated P. aeruginosa lasI mutants appeared to be particularly resistant to serum, whereas bacteria with a functional QS system did not. We show in a CF mouse model of chronic P. aeruginosa lung infection that AZM treatment results in the suppression of QS-regulated virulence factors, significantly improves the clearance of P. aeruginosa alginate biofilms, and reduces the severity of the lung pathology compared to that in control mice. We conclude that AZM attenuates the virulence of P. aeruginosa, impairs its ability to form fully polymerized alginate biofilms, and increases its sensitivity to complement and stationary-phase killing, which may explain the clinical efficacy of AZM.",

author = "Nadine Hoffmann and Baoleri Lee and Morten Hentzer and Rasmussen, {Thomas Bovbjerg} and Zhijun Song and Johansen, {Helle Krogh} and Michael Givskov and Niels H{\o}iby",

note = "Keywords: Alginates; Animals; Anti-Bacterial Agents; Anti-Infective Agents, Local; Azithromycin; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Female; Humans; Hydrogen Peroxide; Lung; Lung Diseases; Male; Mice; Mice, Knockout; Pseudomonas Infections; Pseudomonas aeruginosa; Quorum Sensing; Virulence Factors",

year = "2007",

doi = "10.1128/AAC.01011-06",

language = "English",

volume = "51",

pages = "3677--87",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

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TY - JOUR

T1 - Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice

AU - Hoffmann, Nadine

AU - Lee, Baoleri

AU - Hentzer, Morten

AU - Rasmussen, Thomas Bovbjerg

AU - Song, Zhijun

AU - Johansen, Helle Krogh

AU - Givskov, Michael

AU - Høiby, Niels

N1 - Keywords: Alginates; Animals; Anti-Bacterial Agents; Anti-Infective Agents, Local; Azithromycin; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Female; Humans; Hydrogen Peroxide; Lung; Lung Diseases; Male; Mice; Mice, Knockout; Pseudomonas Infections; Pseudomonas aeruginosa; Quorum Sensing; Virulence Factors

PY - 2007

Y1 - 2007

N2 - The consequences of O-acetylated alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected cystic fibrosis (CF) patients are tolerance to both antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials, azithromycin (AZM) has been shown to improve the lung function of CF patients. The present study was conducted in accordance with previous in vitro studies suggesting that the effect of AZM may be the inhibition of alginate production, blockage of quorum sensing (QS), and increased sensitivity to hydrogen peroxide and the complement system. Moreover, we show that AZM may affect the polymerization of P. aeruginosa alginate by the incomplete precipitation of polymerized alginate and high levels of readily dialyzable uronic acids. In addition, we find that mucoid bacteria in the stationary growth phase became sensitive to AZM, whereas cells in the exponential phase did not. Interestingly, AZM-treated P. aeruginosa lasI mutants appeared to be particularly resistant to serum, whereas bacteria with a functional QS system did not. We show in a CF mouse model of chronic P. aeruginosa lung infection that AZM treatment results in the suppression of QS-regulated virulence factors, significantly improves the clearance of P. aeruginosa alginate biofilms, and reduces the severity of the lung pathology compared to that in control mice. We conclude that AZM attenuates the virulence of P. aeruginosa, impairs its ability to form fully polymerized alginate biofilms, and increases its sensitivity to complement and stationary-phase killing, which may explain the clinical efficacy of AZM.

AB - The consequences of O-acetylated alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected cystic fibrosis (CF) patients are tolerance to both antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials, azithromycin (AZM) has been shown to improve the lung function of CF patients. The present study was conducted in accordance with previous in vitro studies suggesting that the effect of AZM may be the inhibition of alginate production, blockage of quorum sensing (QS), and increased sensitivity to hydrogen peroxide and the complement system. Moreover, we show that AZM may affect the polymerization of P. aeruginosa alginate by the incomplete precipitation of polymerized alginate and high levels of readily dialyzable uronic acids. In addition, we find that mucoid bacteria in the stationary growth phase became sensitive to AZM, whereas cells in the exponential phase did not. Interestingly, AZM-treated P. aeruginosa lasI mutants appeared to be particularly resistant to serum, whereas bacteria with a functional QS system did not. We show in a CF mouse model of chronic P. aeruginosa lung infection that AZM treatment results in the suppression of QS-regulated virulence factors, significantly improves the clearance of P. aeruginosa alginate biofilms, and reduces the severity of the lung pathology compared to that in control mice. We conclude that AZM attenuates the virulence of P. aeruginosa, impairs its ability to form fully polymerized alginate biofilms, and increases its sensitivity to complement and stationary-phase killing, which may explain the clinical efficacy of AZM.

U2 - 10.1128/AAC.01011-06

DO - 10.1128/AAC.01011-06

M3 - Journal article

C2 - 17620382

SN - 0066-4804

VL - 51

SP - 3677

EP - 3687

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 10

ER -