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

IF 2.8 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Thorarinn Gudjonsson , Jon Petur Joelsson , Ari Jon Arason , Arni Asbjarnarson , Fridrik Runar Gardarsson , Fredrik Lehmann , Peter Teodorovic , Saevar Ingthorsson , Snaevar Sigurdsson , Bryndis Valdimarsdottir , Michael John Parnham , Clive Page , Jennifer Ann Kricker
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引用次数: 0

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.
一种新型大环内酯EP395,具有降低抗菌活性和增强呼吸道上皮屏障的作用
上皮屏障功能障碍是几种炎症性肺病的一个特征,可导致病情恶化和疾病进展。急性加重通常用大环内酯类药物治疗,包括阿奇霉素(AZM)。在某种程度上,这是由于主要的抗菌和额外的免疫调节作用,以及最近报道的呼吸上皮屏障完整性增强的补充。然而,长期“标签外”使用大环内酯类药物与细菌耐药性增加有关。我们现在介绍了一类新的化合物,“Barriolides”,它是AZM的类似物,在体外促进气道上皮屏障的完整性,抗菌活性可以忽略不计。先导化合物EP395在100 μM范围内对VA10支气管上皮细胞的活性无影响。用EP395治疗三周后,上皮屏障的完整性增强,测量方法是增加上皮间电阻,减少气液界面培养中的细胞旁通量,增加紧密连接蛋白的表达。EP395还能诱导表皮分化和板层体的形成,并伴有相关的遗传足迹。在暴露于二氧化硫的小鼠中,EP395预处理减少了人血清白蛋白向支气管肺泡灌洗液的外渗。这些数据证明EP395具有上皮屏障保护作用,EP395是治疗慢性呼吸道疾病的有希望的候选药物,没有细菌耐药性的风险。
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来源期刊
CiteScore
6.20
自引率
0.00%
发文量
41
审稿时长
42 days
期刊介绍: Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews. Research Areas Include: • All major diseases of the lung • Physiology • Pathology • Drug delivery • Metabolism • Pulmonary Toxicology.
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