Institute of Microbial Chemistry (BIKAKEN), Tokyo 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
Pharmaceutical Analysis Laboratories, Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 788 Kayama, Odawara-shi 250-0852, Kanagawa, Japan.
ACS Infect Dis. 2023 Apr 14;9(4):886-898. doi: 10.1021/acsinfecdis.2c00557. Epub 2023 Mar 9.
Novel aprosamine derivatives were synthesized for the development of aminoglycoside antibiotics active against multidrug-resistant Gram-negative bacteria. The synthesis of aprosamine derivatives involved glycosylation at the C-8' position and subsequent modification (epimerization and deoxygenation at the C-5 position and 1--acylation) of the 2-deoxystreptamine moiety. All 8'-β-glycosylated aprosamine derivatives (-) showed excellent antibacterial activity against carbapenem-resistant and 16S ribosomal RNA methyltransferase-producing multidrug-resistant Gram-negative bacteria compared to the clinical drug, arbekacin. The antibacterial activity of 5-epi (-) and 5-deoxy derivatives (, and ) of β-glycosylated aprosamine was further enhanced. On the other hand, the derivatives (, and ) in which the amino group at the C-1 position was acylated with ()-4-amino-2-hydroxybutyric acid showed excellent activity (MICs 0.25-0.5 μg/mL) against resistant bacteria that produce the aminoglycoside-modifying enzyme, aminoglycoside 3--acetyltransferase IV, which induces high resistance against parent apramycin (MIC > 64 μg/mL). In particular, and showed approximately 2- to 8-fold antibacterial activity against carbapenem-resistant and 8- to 16-fold antibacterial activity against resistant Gram-positive bacteria, such as methicillin-resistant and vancomycin-resistant , compared to apramycin. Our results showed that aprosamine derivatives have immense potential in the development of therapeutic agents for multidrug-resistant bacteria.
新型阿泊拉霉素衍生物被合成用于开发针对多药耐药革兰氏阴性菌的氨基糖苷类抗生素。阿泊拉霉素衍生物的合成涉及 C-8'位的糖基化，以及随后对 2-脱氧链霉胺部分进行修饰（C-5 位差向异构化和脱氧以及 1-位酰化）。与临床药物阿贝卡星相比，所有 8'-β-糖基化的阿泊拉霉素衍生物（-）对碳青霉烯耐药和 16S 核糖体 RNA 甲基转移酶产生的多药耐药革兰氏阴性菌表现出优异的抗菌活性。β-糖基化阿泊拉霉素的 5-表异构物（5-epi（-））和 5-脱氧衍生物（、和）的抗菌活性进一步增强。另一方面，在 C-1 位的氨基被（）-4-氨基-2-羟基丁酸酰化的衍生物（、和）对产生氨基糖苷修饰酶的耐药菌表现出优异的活性（MICs 0.25-0.5μg/mL），该酶诱导对亲本阿普拉霉素（MIC＞64μg/mL）的高度耐药。特别是，与阿普拉霉素相比，和对碳青霉烯耐药和耐甲氧西林的和万古霉素耐药的革兰氏阳性菌，如耐甲氧西林的和万古霉素耐药的，具有约 2-8 倍和 8-16 倍的抗菌活性。我们的结果表明，阿泊拉霉素衍生物在开发针对多药耐药菌的治疗剂方面具有巨大潜力。
