Effect of Erythromycin on Chronic Respiratory Infection Caused by<i>Pseudomonas aeruginosa</i>with Biofilm Formation in an Experimental Murine Model

Nagata, Towako; Mukae, Hiroshi; Kadota, Jun‐ichi; Hayashi, Tomayoshi; Fujii, Takeshi; Kuroki, Misuzu; Shirai, Ryo; Yanagihara, Katsunori; Tomono, Kazunori; Koji, Takehiko; Kohno, Shigeru

doi:10.1128/aac.48.6.2251-2259.2004

Cited by 42 publications

(29 citation statements)

References 31 publications

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“…When the concentration of such an excreted metabolite reaches its threshold level, certain types of gene expression resulting in bioluminescence [1], biofilm formation [2,3], swarming motility [4], antibiotic biosynthesis [5,6] virulence factor production [7,8], etc., are triggered by the metabolite (autoinducer). Disruption of the QS system in pathogenic Burkholderia cepacia and B. pseudomallei resulted in reduced pathogenicity in murine and hamster infection [9,10], and erythromycin inhibits biofilm formation of Pseudomonas aeruginosa below the minimum inhibitory concentration (MIC) [11]. Therefore, compounds that inhibit QS have great potential for use in the treatment of bacterial infectious diseases.…”

Section: Introductionmentioning

confidence: 99%

Piericidins, Novel Quorum-Sensing Inhibitors against Chromobacterium violaceum CV026, from Streptomyces sp. TOHO-Y209 and TOHO-O348

Ooka¹,

Fukumoto²,

Yamanaka³

et al. 2013

OJMC

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Piericidin A1, 3'-rhamnopiericidin A1, and a novel compound piericidin E, a new quorum-sensing (QS) inhibitor against Chromobacterium violaceum CV026, were isolated from the culture broth of Streptomyces sp. QS is well known as a microbial signaling system and controls certain types of gene expression resulting in bioluminescence, biofilm formation, swarming motility, antibiotic biosynthesis, and virulence factor production. C. violaceum CV026 is commonly used to determine qualitative and quantitative QS activity. The structures of piericidin derivatives were characterized, and their QS activities were determined.

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Section: Introductionmentioning

confidence: 99%

Piericidins, Novel Quorum-Sensing Inhibitors against Chromobacterium violaceum CV026, from Streptomyces sp. TOHO-Y209 and TOHO-O348

Ooka¹,

Fukumoto²,

Yamanaka³

et al. 2013

OJMC

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“…Macrolides were shown to have immunomodulatory activity, which results in a decreased inflammatory response to bacterial stimulation (16), and there have been several studies demonstrating that macrolides inhibit virulence factor production in P. aeruginosa in vitro and in vivo and interfere with biofilm formation (17,18,19,20,21,22).…”

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confidence: 99%

Recycling of Peptidyl-tRNAs by Peptidyl-tRNA Hydrolase Counteracts Azithromycin-Mediated Effects on Pseudomonas aeruginosa

Gödeke

Pustelny

Häußler

2013

Antimicrob Agents Chemother

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Acute and chronic infections caused by the opportunistic pathogen Pseudomonas aeruginosa pose a serious threat to human health worldwide, and its increasing resistance to antibiotics requires alternative treatments that are more effective than available strategies. Clinical studies have clearly demonstrated that cystic fibrosis (CF) patients with chronic P. aeruginosa infections benefit from long-term low-dose azithromycin (AZM) treatment. Immunomodulating activity, the impact of AZM on the expression of quorum-sensing-dependent virulence factors, type three secretion, and motility in P. aeruginosa seem to contribute to the therapeutic response. However, to date, the molecular mechanisms underlying these AZM effects have remained elusive. Our data indicate that the AZM-mediated phenotype is caused by a depletion of the intracellular pools of tRNAs available for protein synthesis. Overexpression of the P. aeruginosa peptidyl-tRNA hydrolase, which recycles the tRNA from peptidyl-tRNA drop-off during translation, counteracted the effects of AZM on stationary-phase cell killing, cytotoxicity, and the production of rhamnolipids and partially restored swarming motility. Intriguingly, the exchange of a rare for a frequent codon in rhlR also explicitly diminished the AZM-mediated decreased production of rhamnolipids. These results indicate that depletion of the tRNA pools by AZM seems to affect the translation of genes that use rare aminoacyl-tRNA isoacceptors to a great extent and might explain the selective activity of AZM on the P. aeruginosa proteome and possibly also on the protein expression profiles of other bacterial pathogens. Pseudomonas aeruginosa is an opportunistic bacterial pathogen that causes both life-threatening acute and devastating chronic infections in the human host (1). In cystic fibrosis (CF) patients, the respiratory tract is especially prone to chronic infections caused by the most dominant bacterial pathogen, P. aeruginosa, and these infections largely determine the fate and prognosis of these patients (2, 3). Improved antimicrobial treatment strategies have greatly increased the life expectancy of CF patients in the last decades. Nevertheless, even aggressive antimicrobial therapy rarely eradicates established chronic P. aeruginosa infections (4, 5, 6). Hence, for the management of chronic infectious diseases, there is a strong need for alternative treatment strategies that amend classical antimicrobial therapy (7,8,9). Several clinical studies have demonstrated that CF patients and patients suffering from diffuse panbronchiolitis (DPB) who are chronically infected with P. aeruginosa benefit from treatment with the macrolide azithromycin (AZM), although the 14-and 15-C macrolides (erythromycin, azithromycin, and clarithromycin) do not inhibit the growth of P. aeruginosa at concentration levels below the breakpoint concentration for susceptibility to the macrolides (10,11,12,13,14,15).The nature of this beneficial effect of AZM is still unclear. Macrolides were shown to have immunomodulatory a...

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“…A murine study by Nagata et al (46) that used plastic tubes precoated with P. aeruginosa as a base for the development of a chronic infection has demonstrated that biofilm formation is suppressed by erythromycin. A favorable modulation of the immune response by AZM has been indicated by Moser et al (45) in a mouse model with seaweed alginate-entrapped P. aeruginosa.…”

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confidence: 99%

Azithromycin Blocks Quorum Sensing and Alginate Polymer Formation and Increases the Sensitivity to Serum and Stationary-Growth-Phase Killing ofPseudomonas aeruginosaand Attenuates ChronicP. aeruginosaLung Infection inCftr⁻^/⁻Mice

Hoffmann

Lee

Hentzer

et al. 2007

Antimicrob Agents Chemother

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182

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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.Mucoid Pseudomonas aeruginosa plays an important role in chronic lung infections among patients with CF due to its ability to form alginate-producing biofilms, which enable the bacteria to resist treatments with antibiotics and which affect the actions of the cells of the immune system (23). Macrolides such as azithromycin (AZM) are normally used against grampositive bacteria, whereas many gram-negative rods, such as Pseudomonas spp., are inherently resistant to macrolides (56). However, several clinical studies from Japan (36, 39, 65) have highlighted the beneficial effects of different macrolides, including AZM, in the treatment of patients with diffuse panbronchiolitis, a disease which is very similar to CF. The first indication that AZM therapy could also benefit the lung function in CF patients was given by Jaffe et al. (27) and was subsequently confirmed by other investigators (9,16,58,74). The mechanisms of action macrolides are multiple and may include an anti-inflammatory effect (36, 40), inhibition of a key enzyme in the alginate synthesis pathway (47), modulation of the production of quorum-sensing (QS) bacterial virulence factors (33,44,69), and/or inhibition of protein synthesis after prolonged exposure (67, 68).In P. aeruginosa, the production of several virulence factors is regulated by cell-to-cell communication, based on the lasand rhl-encoded QS systems (6), w...

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Effect of Erythromycin on Chronic Respiratory Infection Caused byPseudomonas aeruginosawith Biofilm Formation in an Experimental Murine Model

Cited by 42 publications

References 31 publications

Piericidins, Novel Quorum-Sensing Inhibitors against Chromobacterium violaceum CV026, from Streptomyces sp. TOHO-Y209 and TOHO-O348

Piericidins, Novel Quorum-Sensing Inhibitors against Chromobacterium violaceum CV026, from Streptomyces sp. TOHO-Y209 and TOHO-O348

Recycling of Peptidyl-tRNAs by Peptidyl-tRNA Hydrolase Counteracts Azithromycin-Mediated Effects on Pseudomonas aeruginosa

Azithromycin Blocks Quorum Sensing and Alginate Polymer Formation and Increases the Sensitivity to Serum and Stationary-Growth-Phase Killing ofPseudomonas aeruginosaand Attenuates ChronicP. aeruginosaLung Infection inCftr⁻^/⁻Mice

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Effect of Erythromycin on Chronic Respiratory Infection Caused byPseudomonas aeruginosawith Biofilm Formation in an Experimental Murine Model

Cited by 42 publications

References 31 publications

Piericidins, Novel Quorum-Sensing Inhibitors against Chromobacterium violaceum CV026, from Streptomyces sp. TOHO-Y209 and TOHO-O348

Piericidins, Novel Quorum-Sensing Inhibitors against Chromobacterium violaceum CV026, from Streptomyces sp. TOHO-Y209 and TOHO-O348

Recycling of Peptidyl-tRNAs by Peptidyl-tRNA Hydrolase Counteracts Azithromycin-Mediated Effects on Pseudomonas aeruginosa

Azithromycin Blocks Quorum Sensing and Alginate Polymer Formation and Increases the Sensitivity to Serum and Stationary-Growth-Phase Killing ofPseudomonas aeruginosaand Attenuates ChronicP. aeruginosaLung Infection inCftr−/−Mice

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Resources

About

Azithromycin Blocks Quorum Sensing and Alginate Polymer Formation and Increases the Sensitivity to Serum and Stationary-Growth-Phase Killing ofPseudomonas aeruginosaand Attenuates ChronicP. aeruginosaLung Infection inCftr⁻^/⁻Mice