硬度和充电模组的配置在化两型聚烯螺旋内对细胞透和抗生素活性的影响
Andrew Encinas1, Reena Blade1, Nader S Abutaleb2,3
1Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2027, United States.
ACS infectious diseases
|July 26, 2024
概括
新的阴性两性聚烯螺旋 (CAPHs) 有效地向细胞内细菌. 通过增强刚性和缩短侧链的修改,显著提高了对MRSA和沙门氏菌的抗菌活性.
科学领域:
- 药用化学 医学化学
- 分子生物学分子生物学
- 抗菌研究 抗菌研究
背景情况:
- 哺乳动物细胞内存在的致病细菌由于其受保护的细胞内环境而构成治疗挑战.
- 开发新的分子策略对于有效向这些细胞内病原体至关重要.
- 目前的治疗方法往往难以透宿主细胞并达到居住在其中的细菌.
研究的目的:
- 作为向细胞内细菌的策略,研究阴性两性聚烯螺旋 (CAPHs).
- 评估结构修改的影响,特别是不自然的プロ林残留物的刚性和侧链配置,对CAPH的疗效.
- 评估修改后的CAPHs对细胞内病原体的抗菌活性,如耐甲基金黄色葡萄球菌 (MRSA) 和沙门氏菌.
主要方法:
- 一系列CAPHs的合成和表征,其刚度不同,并具有非自然的proline配置.
- 在巨模型中评估不同CAPH变异的细胞吸收效率.
- 对CAPHs对细胞内MRSA和沙门氏菌感染的抗菌疗效的评估.
- 对修改CAPH与原始CAPH和标准治疗的性能进行比较分析.
主要成果:
- 缩短guanidinium侧链和聚烯螺旋体脊柱之间的距离显著增强了细胞吸收和抗菌活性.
- 从cis改为trans的pyrrolidine环部分的配置进行修改,在活性方面取得了较为温和的改善.
- 优化,刚性CAPH在消除巨细胞内的细胞内MRSA和沙门氏菌感染方面表现出异常的有效性.
- 增强的CAPH在清除细胞内细菌感染方面明显优于母CAPH.
结论:
- 结构刚性和优化的侧链放置对于开发有效的基于CAPH的抗菌药物至关重要.
- 修改后的CAPHs代表了对抗具有挑战性的细胞内细菌感染的有希望的治疗类.
- 这项研究为设计下一代针对宿主细胞内的细菌的抗微生物药物提供了基础.
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