体内
抗生素
效力
抗生素耐药性
微生物学
肉豆蔻酸
生物
部分
化学
生物化学
药理学
体外
立体化学
生物技术
脂肪酸
棕榈酸
作者
Adam Rosenzweig,Kaylyn Spotton,Abir Bhattacharjee,Adrián Morales-Amador,Sean F. Brady
出处
期刊:ACS Infectious Diseases
[American Chemical Society]
日期:2024-04-16
卷期号:10 (5): 1536-1544
标识
DOI:10.1021/acsinfecdis.4c00018
摘要
Cilagicin is a dual polyprenyl phosphate binding lipodepsipeptide antibiotic with strong activity against clinically relevant Gram-positive pathogens while evading antibiotic resistance. Cilagicin showed high serum binding that reduced its in vivo efficacy. Cilagicin-BP, which contains a biphenyl moiety in place of the N-terminal myristic acid found on cilagicin, showed reduced serum binding and increased in vivo efficacy but decreased potency against some pathogens. Here, we manipulated the acyl tail and the peptide core of cilagicin to identify an optimized collection of structural features that maintain potent antibiotic activity against a wide range of pathogens in the presence of serum. This led to the identification of the optimized antibiotic dodecacilagicin, which contains an N-terminal dodecanoic acid. Dodecacilagicin exhibits low MICs against clinically relevant pathogens in the presence of serum, retains polyprenyl phosphate binding, and evades resistance development even after long-term antibiotic exposure, making dodecacilagicin an appealing candidate for further therapeutic development.
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