通过循环和立体化学倒置克服β-Turn抗菌中的蛋白质溶解不稳定性,以对抗MDR细菌
Taoran Wang1,2, Long Tian1,2, Jiangmin Zeng1,2
1Academy of Military Medical Sciences, No. 27 Taiping Road, Haidian District, Beijing 100850, China.
Journal of medicinal chemistry
|February 17, 2026
概括
研究人员使用循环和d-氨基酸设计了稳定的抗微生物 (AMP). 新的PT-17对具有低毒性的耐药细菌表现出强烈的活性,为新抗生素提供了有前途的战略.
科学领域:
- 生物化学 生物化学
- 药用化学 医学化学
- 微生物学 微生物学
背景情况:
- 开发蛋白质分解稳定的抗微生物 (AMP) 对于解决抗生素耐药性至关重要.
- 循环稳定AMP,但其对β转AMP结构-活性关系的影响不太清楚.
研究的目的:
- 为了设计β转AMP P-07的循环衍生物.
- 研究循环化和d-氨基酸替代对AMP稳定性和活性的影响.
主要方法:
- 使用二硫化物/乳酸键循环和d-氨基酸替代的P-07的工程循环衍生物.
- 评估稳定性,对抗多药耐药 (MDR) 病原体的广泛活性,以及衍生品的治疗指数.
- 评估了膜破坏,耐药性诱导潜力和与常规抗生素的协同作用.
- 在小鼠感染模型中测试了有效性.
主要成果:
- 主要候选者PT-17显著增强稳定性和对MDR病原体的强大广泛活性.
- PT-17具有高的治疗指数,快速破坏膜,并具有诱导细菌耐药性的低潜力.
- 当PT-17与常规抗生素结合使用时,观察到协同效应.
- 在体内研究表明,PT-17有效地降低了小鼠中的大肠杆菌负载,没有可检测的毒性.
结论:
- 循环和d-氨基酸替代协同增强β转AMP的稳定性,而不会影响其活性.
- PT-17代表了一种可行的策略,用于开发具有重大临床潜力的新型AMP,用于打击抗生素耐药性.
相关概念视频
Protein Folding
11.7K
Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
11.7K
Bacterial Protein Maturation
595
Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...
595


