GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovića 29, Zagreb, Croatia.
J Med Chem. 2012 Jul 12;55(13):6111-23. doi: 10.1021/jm300356u. Epub 2012 Jun 25.
Macrolide antibiotics, like erythromycin, clarithromycin, and azithromycin, possess anti-inflammatory properties. These properties are considered fundamental to the efficacy of these three macrolides in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, long-term treatment with macrolide antibiotics presents a considerable risk for promotion of bacterial resistance. We have examined antibacterial and anti-inflammatory effects of a novel macrolide class: N'-substituted 2'-O,3'-N-carbonimidoyl bridged erythromycin-derived 14- and 15-membered macrolides. A small focused library was prepared, and compounds without antimicrobial activity, which inhibited IL-6 production, were selected. Data analysis led to a statistical model that could be used for the design of novel anti-inflammatory macrolides. The most promising compound from this library retained the anti-inflammatory activity observed with azithromycin in lipopolysaccharide-induced pulmonary neutrophilia in vivo. Importantly, this study strongly suggests that antimicrobial and anti-inflammatory activities of macrolides are independent and can be separated, which raises development plausibility of novel anti-inflammatory therapeutics.
大环内酯类抗生素，如红霉素、克拉霉素和阿奇霉素，具有抗炎特性。这些特性被认为是这三种大环内酯类药物在治疗弥漫性泛细支气管炎和囊性纤维化等慢性炎症性疾病中的疗效的基础。然而，长期使用大环内酯类抗生素会极大地增加细菌耐药性的风险。我们研究了一种新型大环内酯类抗生素的抗菌和抗炎作用：N'-取代的 2'-O、3'-N-碳亚氨基桥连的红霉素衍生的 14 元和 15 元大环内酯类。我们制备了一个小的聚焦文库，并选择了没有抗菌活性但能抑制白细胞介素 6 产生的化合物。数据分析导致了一个统计模型，可用于设计新型抗炎大环内酯类药物。该文库中最有前途的化合物保留了与阿奇霉素相似的抗炎活性，可抑制脂多糖诱导的体内肺中性粒细胞增多。重要的是，这项研究强烈表明，大环内酯类的抗菌和抗炎活性是独立的，可以分离，这增加了新型抗炎治疗药物的开发可能性。
