Development of non-antibiotic macrolide that corrects inflammation-driven immune dysfunction in models of inflammatory bowel diseases and arthritis

Mencarelli, Andrea; Distrutti, Eleonora; Renga, Barbara; Cipriani, Sabrina; Palladino, Giuseppe; Booth, Catherine; Tudor, Gregory; Guse, Jan-Hinrich; Hahn, Ulrike; Burnet, Micheal; Fiorucci, Stefano

doi:10.1016/j.ejphar.2011.04.036

Cited by 53 publications

(41 citation statements)

References 37 publications

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“…This effective treatment might be due to an immunomodulatory activity that reduces bronchiolar inflammation and damage (41). However, AZM also significantly influences bacterial production of virulence factors and has an impact on biofilm formation (18,42).…”

Section: Fig 2 Azm-mediated Killing Of Pa14 Wild-type Control and Pthmentioning

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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Section: Fig 2 Azm-mediated Killing Of Pa14 Wild-type Control and Pthmentioning

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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show abstract

“…In addition to erythromycin A, the prototype macrolide, 16 several other macrolides, clarithromycin and roxithromycin are 17 clinically available (Payne et al, 2007). Besides its antibacterial 18 activity, macrolides exert diverse biological effects including the 19 ability to modulate inflammatory and immune responses without 20 affecting homeostatic immunity (Mencarelli et al, 2011). More 21 recently, macrolides have been also considered for other uses in 22 the areas of neurology, gastroenterology, rheumatology, cardiolo-23 gy, and cancer therapy, facilitating the development of new 24 synthetic methods as well as the design of new therapeutic agents 25 possessing non-antibacterial activities (Miroshnyk et al, 2008).…”

mentioning

confidence: 99%

Microbiological assay for the analysis of certain macrolides in pharmaceutical dosage forms

Mahmoudi

Fourar

Boukhechem

et al. 2015

International Journal of Pharmaceutics

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“…50% in untreated animals. 23 Both CSY0073 and azithromycin have similar potency in assays on the response of cultured cells, airways, the gut lining or lamina propria cells to stimulation with LPS. Given that this effect occurs on a time-scale of minutes to hours and that it is not dependent on the presence of bacteria, there is a reasonable possibility that both compounds are acting on independent pathways of macrolide effect that include direct anti-inflammatory action.…”

Section: Is the Anti-inflammatory Activity Of Macrolidesmentioning

confidence: 94%

“…23,28 Downstream effects include interference with the nuclear expression of activator protein-1 (AP-1) 4 and NFkB. 29 Azithromycin reduces IL-12p40 transcriptional activity by inhibiting the binding of AP-1 to the promoter site.…”

Section: Molecular Mechanisms Of Macrolide Modulation Of Inflammationmentioning

confidence: 99%

Anti-Inflammatory Macrolides to Manage Chronic Neutrophilic Inflammation

Burnet

Guse

Gutke

et al. 2014

Macrocycles in Drug Discovery

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Macrolide antibiotics, notably azithromycin, have clinically useful effects in a range of inflammatory diseases and especially those of the lung. Effects include a reduction of inflammatory cytokines, reductions in neutrophil infiltration and potentially a polarisation of infiltrating cells to a pro-resolution phenotype. The mode of action behind this effect is unlikely to be a single interaction and may involve reductions in prostaglandin synthesis via phospholipase inhibition, modulation of NFκB translocation, reduction in IL-8 production and reduction in reflux aspiration to the airways. While some of the clinical effects can be rationalised through antibacterial actions leading to changes in normal flora and reducing Pseudomonads in particular, there is also evidence for effects unrelated to antibacterial actions that appear to relate to reductions in neutrophil activation, potentially related to high accumulation in neutrophil lysosomes. Concerted efforts to improve on these effects have focused on either generating non-antibacterial analogues, or in conjugating anti-inflammatory drugs to the macrolide backbone. Both approaches have provided strong pre-clinical data suggesting that the selective disposition of macrolides to inflamed tissue, as well as their pleiotropic effects on immune cells, contribute to their broad anti-inflammatory effects. The more recent observations of stronger macrolide effects in the context of neutrophil-mediated disease and corresponding effects on IL-17 positive cells in tissue suggest that it may be possible to select patients likely to respond to macrolide therapy. The discovery of non-antibacterial macrolides that preserve this anti-inflammatory effect provides a means to bring these effects more broadly to the clinic without selecting for large-scale resistance to antibacterial macrolides or to other anti-infectives via cross-resistance.

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Development of non-antibiotic macrolide that corrects inflammation-driven immune dysfunction in models of inflammatory bowel diseases and arthritis

Cited by 53 publications

References 37 publications

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

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

Microbiological assay for the analysis of certain macrolides in pharmaceutical dosage forms

Anti-Inflammatory Macrolides to Manage Chronic Neutrophilic Inflammation

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