Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.
Department of Microbial Pathogenesis, University of Maryland, Baltimore, MD, USA.
Eur J Med Chem. 2023 May 5;253:115329. doi: 10.1016/j.ejmech.2023.115329. Epub 2023 Mar 31.
The Centers for Disease Control and Prevention (CDC) reports that hospital acquired infections have increased by 65% since 2019. One of the main contributors is the gram-negative bacterium Acinetobacter baumannii. Previously, we reported aryl 2-aminoimidazole (2-AI) adjuvants that potentiate macrolide antibiotics against A. baumannii. Macrolide antibiotics are typically used to treat infections caused by gram-positive bacteria, but are ineffective against most gram-negative bacteria. We describe a new class of dimeric 2-AIs that are highly active macrolide adjuvants, with lead compounds lowering minimum inhibitory concentrations (MICs) to or below the gram-positive breakpoint level against A. baumannii. The parent dimer lowers the clarithromycin (CLR) MIC against A. baumannii 5075 from 32 μg/mL to 1 μg/mL at 7.5 μM (3.4 μg/mL), and a subsequent structure activity relationship (SAR) study identified several compounds with increased activity. The lead compound lowers the CLR MIC to 2 μg/mL at 1.5 μM (0.72 μg/mL), far exceeding the activity of both the parent dimer and the previous lead aryl 2-AI. Furthermore, these dimeric 2-AIs exhibit considerably reduced mammalian cell toxicity compared to aryl-2AI adjuvants, with ICs of the two lead compounds against HepG2 cells of >200 μg/mL, giving therapeutic indices of >250.
疾病控制与预防中心（CDC）报告称，自 2019 年以来，医院获得性感染增加了 65%。其中一个主要原因是革兰氏阴性菌鲍曼不动杆菌。此前，我们报道了芳基 2-氨基咪唑（2-AI）佐剂，可增强大环内酯类抗生素对鲍曼不动杆菌的作用。大环内酯类抗生素通常用于治疗由革兰氏阳性菌引起的感染，但对大多数革兰氏阴性菌无效。我们描述了一类新的二聚 2-AI，它们是高效的大环内酯类抗生素佐剂，其先导化合物将最低抑菌浓度（MIC）降低至或低于鲍曼不动杆菌的革兰氏阳性折点水平。母体二聚体将克拉霉素（CLR）对鲍曼不动杆菌 5075 的 MIC 从 32μg/mL 降低至 7.5μM（3.4μg/mL）时的 1μg/mL，随后的构效关系（SAR）研究确定了几种活性增强的化合物。先导化合物将 CLR 的 MIC 降低至 1.5μM（0.72μg/mL）时的 2μg/mL，远远超过母体二聚体和之前的芳基 2-AI 先导化合物的活性。此外，与芳基-2AI 佐剂相比，这些二聚 2-AI 的哺乳动物细胞毒性大大降低，两种先导化合物对 HepG2 细胞的 IC 大于 200μg/mL，治疗指数大于 250。
