Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep:90:102363.
doi: 10.1016/j.pupt.2025.102363. Epub 2025 Jun 3.

A novel macrolide, EP395, with reduced antibacterial activity and an enhancing effect on respiratory epithelial barrier

Thorarinn Gudjonsson  1 , Jon Petur Joelsson  1 , Ari Jon Arason  1 , Arni Asbjarnarson  1 , Fridrik Runar Gardarsson  2 , Fredrik Lehmann  2 , Peter Teodorovic  2 , Saevar Ingthorsson  3 , Snaevar Sigurdsson  3 , Bryndis Valdimarsdottir  2 , Michael John Parnham  2 , Clive Page  4 , Jennifer Ann Kricker  5
Affiliations
Free article

A novel macrolide, EP395, with reduced antibacterial activity and an enhancing effect on respiratory epithelial barrier

Thorarinn Gudjonsson et al. Pulm Pharmacol Ther. 2025 Sep.
Free article

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.

Keywords: Azithromycin; COPD; EP395; Epithelial barrier; Gene expression; Macrolides.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AA, AJA, BV, FL, FRG, JAK, JPJ, MJP, PT, SI, SS, TG reports financial support was provided by EpiEndo Pharmaceuticals ehf. JK, AA, AJA, BV, JPJ, FRG, MJP, SI, TG reports financial support was provided by The Icelandic Center for Research. MJP reports a relationship with Sound Bioventures that includes: consulting or advisory. MJP reports a relationship with Phiaologics AG that includes: equity or stocks. MJP reports a relationship with Cyclone Inc that includes: equity or stocks. MJP reports a relationship with Immune Age BIO Inc that includes: equity or stocks. JAK, AJA, BV, CP, FRG, FL, JPJ, MJP, PT, SI, TG reports a relationship with EpiEndo Pharmaceuticals that includes: equity or stocks. CP reports a relationship with Ananda Developments plc that includes: consulting or advisory. CP reports a relationship with EpiEndo Pharmaceuticals ehf. that includes: consulting or advisory. CP reports a relationship with MicroA that includes: consulting or advisory. FL reports a relationship with Recipharm OT Chemistry that includes: consulting or advisory. FRG, FL, PT have a patent #WO/2017/085329 issued to EpiEndo Pharmaceuticals. MJP co-author previously employed by GSK and Pliva - MJP co-author is Editor-in-Chief in Inflammation Research - MJP co-author is an Honorary editor of Pulmonary Pharmacology - CP co-author is previous Editor in Chief for Pulmonary Pharmacology & Therapeutics. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

LinkOut - more resources