通过使用非蛋白质氨基酸对抗微生物的结构修改来增强化学稳定性
Takahito Ito1,2, Natsumi Matsunaga1, Megumi Kurashima1
1National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki-shi 210-9501, Japan.
Antibiotics (Basel, Switzerland)
|August 26, 2023
概括
新的抗微生物 (AMP) 抗击耐药细菌. 用Api替换氨酸增强了酶耐药性,并保持了抗菌活性,为传染病提供了有前途的解决方案.
科学领域:
- 生物化学 生物化学
- 微生物学 微生物学
- 药物发现 药物发现 药物发现
背景情况:
- 耐多药细菌 (MDRB) 每年导致超过120万人的死亡,需要新的治疗策略.
- 抗微生物 (AMP) 是下一代治疗药物的有希望的类别,因为它们的膜向机制和降低了耐药性发展.
- 之前的工作产生了17KKV-Aib,一种AMP衍生物,对MDRB有强烈的活性,但对消化酶的稳定性有限.
研究的目的:
- 设计和合成新型的17KKV-Aib衍生物,其中包括4-aminopiperidine-4-carboxylic acid (Api) 残留物.
- 评估Api替代对二次结构,抗微生物疗效,溶血活性和酶稳定性的影响.
- 通过提高AMP对降解的抵抗力来增强AMP的治疗潜力.
主要方法:
- 类合成涉及用循环脱代氨基酸 (Api) 替代 lysine 残留物.
- 使用光谱技术分析二次结构.
- 对包括MDRB在内的格拉姆阳性和格拉姆阴性细菌的抗微生物活性评估.
- 对人类红细胞的血液溶解活性的评估.
- 确定对常见消化酶的耐药性.
主要成果:
- 艾比替代保留了AMP的螺旋式二次结构.
- 修改Api的保留了对包括MDRB在内的一系列细菌的强烈抗菌活性.
- 在Api衍生品中观察到对消化酶的增强抵抗力.
- 与母相比,血解活性略有增加.
结论:
- 加入Api残留物是改善AMP抗酶降解稳定的可行策略.
- 经API修改的AMP显示了抗微生物有效性和增强的稳定性,使其更适合治疗应用.
- 这些发现有助于开发更强大的基于AMP的治疗方法来对抗具有挑战性的细菌感染.
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