A novel macrolide, EP395, with reduced antibacterial activity and an enhancing effect on respiratory epithelial
Thorarinn Gudjonsson1, Jon Petur Joelsson1, Ari Jon Arason1
1EpiEndo Pharmaceuticals Ehf., Bjargargata 1, 102, Reykjavik, Iceland; University of Iceland, Faculty of Medicine and Landspitali, 101, Reykjavik, Iceland.
Abstract:
Epithelial barrier failure, a feature of several inflammatory lung diseases, contributes to exacerbations and disease progression. Acute exacerbations are often treated with macrolides, including azithromycin (AZM). In part, this is due to both primary antimicrobial and additional immunomodulatory actions, complemented by recently reported enhanced integrity of respiratory epithelial barriers. However, long-term "off label" use of macrolides is associated with increased bacterial resistance. We now introduce a new class of compounds, "Barriolides" that are analogues of AZM promoting airway epithelial barrier integrity in vitro, with negligible antibacterial activity. The lead compound is EP395 which does not affect cell viability up to 100 μM in VA10 bronchial epithelial cells. Treatment with EP395 for three weeks enhanced epithelial barrier integrity, measured by increased transepithelial electrical resistance, reduced paracellular flux in air-liquid interface culture and increased expression of tight junction proteins. EP395 also induced epidermal differentiation and formation of lamellar bodies, complemented by a relevant genetic footprint. In mice exposed to sulphur dioxide, pre-treatment with EP395 reduced extravasation of human serum albumin into the bronchoalveolar lavage fluid. These data demonstrate epithelial barrier-protecting effects of EP395, a promising candidate for treatment of chronic respiratory diseases without risk of bacterial resistance.
Insights
New barriolides, like EP395, enhance airway epithelial barrier integrity without causing bacterial resistance. This offers a promising therapeutic strategy for chronic respiratory diseases, unlike long-term macrolide use.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Pharmacology
Background:
- Epithelial barrier dysfunction is central to inflammatory lung diseases, exacerbating conditions.
- Macrolides like azithromycin (AZM) treat exacerbations but long-term use risks bacterial resistance.
- AZM's benefits include antimicrobial and immunomodulatory effects, plus improved epithelial barrier function.
Purpose of the Study:
- To introduce a novel class of compounds, "Barriolides," analogues of AZM.
- To evaluate the lead compound EP395 for its ability to promote airway epithelial barrier integrity.
- To assess EP395's efficacy without inducing bacterial resistance.
Main Methods:
- In vitro assessment of EP395 on bronchial epithelial cells (VA10).
- Measurement of epithelial barrier integrity via transepithelial electrical resistance and paracellular flux.
- Analysis of tight junction protein expression, epidermal differentiation, and lamellar body formation.
- In vivo study in mice exposed to sulfur dioxide to assess EP395's protective effects.
Main Results:
- EP395 (up to 100 μM) did not affect bronchial epithelial cell viability.
- Three weeks of EP395 treatment significantly enhanced epithelial barrier integrity.
- EP395 increased tight junction proteins, induced epidermal differentiation, and lamellar body formation.
- EP395 pre-treatment in mice reduced protein extravasation in bronchoalveolar lavage fluid.
Conclusions:
- EP395, a barriolide, effectively enhances airway epithelial barrier integrity.
- EP395 demonstrates therapeutic potential for chronic respiratory diseases.
- This compound offers a strategy to improve barrier function without the risk of antibiotic resistance.
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