Arylomycin analogs are provided, wherein the analogs can have broad spectrum bioactivity. Resistance to the antibiotic bioactivity of natural product arylomycin in a range of pathogenic bacterial species has been found to depend upon single amino acid mutations at defined positions of bacterial Signal Peptidases (SPases), wherein the presence of a proline residue confers arylomycin resistance. Arylomycin analogs are provided herein that can overcome that resistance and provide for a broader spectrum of antibiotic bioactivity than can natural product arylomycins such as arylomycin A2. Methods for determining if a bacterial strain is susceptible to narrow spectrum arylomycin antibiotics, or if a broad spectum analog is required for treatment, is provided. Pharmaceutical compositions and methods of treatment of bacterial infections, and methods of synthesis of arylomycin analogs, are provided.
提供了芳基霉素类似物,其中这些类似物可以具有广谱
生物活性。已发现在一系列致病性细菌物种中,对
天然产物芳基霉素的抗生素活性的抗性取决于细菌信号肽酶(
SPases)的特定位置的单个
氨基酸突变,其中脯
氨酸残基的存在赋予了芳基霉素抗性。本文提供了可以克服该抗性并提供比芳基霉素A2等
天然产物芳基霉素更广谱抗生素活性的芳基霉素类似物。提供了用于确定细菌菌株是否对窄谱芳基霉素抗生素敏感,或者是否需要广谱类似物进行治疗的方法。提供了用于治疗细菌感染的药物组合物和方法,以及芳基霉素类似物的合成方法。