半合成聚米克辛具有强大的抗菌活性,并降低了细胞毒性
Cornelis J Slingerland1, Vladyslav Lysenko1, Samhita Chaudhuri1
1Biological Chemistry Group, Institute of Biology Leiden, Leiden University Sylviusweg 72 2333 BE Leiden The Netherlands n.i.martin@biology.leidenuniv.nl.
RSC medicinal chemistry
|November 17, 2023
概括
新的半合成聚米克辛可以对抗多药物耐药的格拉姆阴性细菌,毒性降低. 这些新型化合物对抗抗菌素耐药性感染有前途,并与其他抗生素协同作用.
科学领域:
- 微生物学 微生物学
- 传染性疾病 传染性疾病
- 药用化学 医学化学
背景情况:
- 越来越多的抗药性格拉姆阴性细菌感染需要最后的抗生素,如多胺.
- 聚米辛治疗受到显著毒性的阻碍,特别是毒性.
- 之前的研究通过修改N端引入了半合成的多杂素,其毒性通过修改N端而降低.
研究的目的:
- 为了进一步降低毒性,探索与多素宏循环相邻的修改.
- 识别具有强大的抗菌活性和更好的安全概况的新型半合成聚米辛.
- 评估新型聚米辛与其他抗生素对抗耐药细菌的协同作用潜力.
主要方法:
- 新型半合成聚密辛的合成,其氨基酸残留在宏观循环附近的变化.
- 对抗格拉姆阴性细菌的抗菌活性的评估,包括对多素耐药菌株.
- 在人类近接管上皮细胞中对毒性的评估.
- 测试与诺波素,里芬素和红色素对mcr阳性大肠杆菌的协同作用.
主要成果:
- 识别新的半合成聚米克辛,保持与聚米克辛B相当的强效抗菌活性.
- 与之前的类似物相比,进一步减少了对人类近接管道上皮细胞的毒性.
- 在新型聚ymyxins 和 novobiocin, rifampicin 或 erythromycin 之间观察到有效的协同作用,以对抗 mcr-阳性,抗聚myxin 的 E. coli.
结论:
- 修改邻聚胺宏循环的氨基酸残留物产生强效,毒性较低的半合成衍生物.
- 这些新型的多种菌素提供了一种有前途的治疗策略,可以对抗具有挑战性的多药耐药性格兰氏阴性感染.
- 对抗多素耐药菌株的协同潜力是克服耐药机制的可行方法.
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