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上海藥物所研發新型硫鎓修飾糖肽抗生素

文章來源:上海藥物研究所   發布時間:2019-03-29  【字號:     】  

  目前全世界每年有70萬人死于耐藥細菌的感染。萬古霉素耐藥的金黃色葡萄球菌(VISA,VRSA)和腸球菌(VRE)被世界衛生組織(WHO)列入亟需新型抗生素的12種重要耐藥菌之中。

  中國科學院上海藥物研究所黃蔚、藍樂夫和宮麗崑研究團隊針對耐藥菌感染的重大臨床需求,積極研發新型糖肽抗生素,在前期研究中采用糖脂修飾策略和焦磷酸靶向策略發展了更為安全有效的抗耐藥菌候選新藥SM-V-61(J. Med. Chem. 2018, 286,ChemMedChem 2018, 1644)。最近,該研究團隊針對萬古霉素的結構骨架,分別在萬古糖胺、間二苯酚、C-端和N-端等4個修飾位點,引入硫鎓分子片段,設計合成了一系列新型糖肽抗生素類似物。體外的藥效學研究,這一策略被證明能有效地提高萬古霉素的抗耐藥菌活性,最高達到萬古霉素的2048倍以上。該策略不僅對與萬古霉素高度耐藥的革蘭氏陽性菌VRE有效,而且對某些革蘭氏陰性菌也具有一定的效果。作用機制方面的研究表明,硫鎓修飾的糖肽抗生素能有效增加細菌細胞膜的通透性,造成去極化,破壞細胞膜的完整性,從而有效提高抗耐藥菌活性。體內藥代動力學研究表明,硫鎓糖肽抗生素能有效提高藥物曝露量(AUC),同時保持適中的體內清除率,避免積蓄毒性。在腎細胞毒性實驗中,硫鎓衍生物對比硫醚修飾或季銨鹽正離子修飾的化合物具有更高的安全性。整體上,基于硫鎓離子修飾的結構優化策略是有效的、安全的,具有良好的成藥性特點,是藥物化學中被低估的重要策略之一。該工作不僅為對抗多重耐藥菌感染提供了新的糖肽抗生素結構,而且為藥物化學結構改造策略提供了新穎的硫鎓修飾應用。

  該研究工作于3月25日在線發表于《德國應用化學》(Angew. Chem. Int. Ed.),文章第一作者是上海藥物所博士研究生管棟梁。此課題獲得國家自然科學基金委和國家重大新藥創制項目的支持。

  論文鏈接

 

硫鎓修飾的糖肽抗生素對抗耐藥菌的作用機制 

 

硫鎓糖肽抗生素5d的體內抗耐藥菌活性。(A)MRSA感染小鼠(B)VISA感染小鼠 




(責任編輯:葉瑞優)

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