Approximately 1.7 million Americans develop hospital associated infections each year, resulting in more than 98,000 deaths. One of the main contributors to such infections is the Gram-negative pathogen Acinetobacter baumannii. Recently, it was reported that aryl 2-aminoimidazole (2-AI) compounds potentiate macrolide antibiotics against a highly virulent strain of A. baumannii, AB5075. The two lead compounds in that report increased clarithromycin (CLR) potency against AB5075 by 16-fold, lowering the minimum inhibitory concentration (MIC) from 32 to 2 μg/mL at a concentration of 10 μM. Herein, we report a structure–activity relationship study of a panel of derivatives structurally inspired by the previously reported aryl 2-AI leads. Substitutions around the core phenyl ring yielded a lead that potentiates clarithromycin by 64- and 32-fold against AB5075 at 10 and 7.5 μM, exceeding the dose response of the original lead. Additional probing of the amide linker led to the discovery of two urea containing adjuvants that suppressed clarithromycin resistance in AB5075 by 64- and 128-fold at 7.5 μM. Finally, the originally reported adjuvant was tested for its ability to suppress the evolution of resistance to clarithromycin over the course of nine consecutive days. At 30 μM, the parent compound reduced the CLR MIC from 512 to 2 μg/mL, demonstrating that the original lead remained active against a more CLR resistant strain of AB5075.

中文翻译：

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增强大环内酯类佐剂对鲍曼不动杆菌的活性。

每年约有 170 万美国人发生与医院相关的感染，导致超过 98,000 人死亡。导致此类感染的主要因素之一是革兰氏阴性病原体鲍曼不动杆菌。最近，据报道，芳基 2-氨基咪唑 (2-AI) 化合物可增强大环内酯类抗生素对高毒力鲍曼不动杆菌菌株的作用。, AB5075。该报告中的两种先导化合物将克拉霉素 (CLR) 对 AB5075 的效力提高了 16 倍，在 10 μM 浓度下将最小抑制浓度 (MIC) 从 32 降低到 2 μg/mL。在此，我们报告了一组衍生物的构效关系研究，该研究在结构上受到先前报道的芳基 2-AI 前导的启发。核心苯环周围的取代产生了一种铅，在 10 和 7.5 μM 时，克拉霉素对 AB5075 的作用分别提高了 64 倍和 32 倍，超过了原始铅的剂量反应。对酰胺接头的额外探测导致发现了两种含尿素的佐剂，它们在 7.5 μM 时将 AB5075 中的克拉霉素抗性抑制了 64 倍和 128 倍。最后，对最初报道的佐剂在连续 9 天内抑制对克拉霉素耐药性演变的能力进行了测试。在 30 μM 时，母体化合物将 CLR MIC 从 512 降低到 2 μg/mL，表明原始铅对更耐 CLR 的 AB5075 菌株保持活性。