設計與合成鐵載體－螢光基團共軛物與雙重抗生素共軛物

Abstract

共軛(conjugation)是一種泛用的策略以合成具生物活性的分子。在此論文中，我們合成兩種共軛化合物，分別是鐵載體－螢光基團共軛物與雙重抗生素共軛物。 鐵載體是一類由細菌在缺鐵環境下分泌的次級代謝物。微生物對於鐵載體的攝取具有高度選擇性，因此鐵載體與抗生素或螢光基團生成的共軛物已被大量報導，並具有廣泛的應用。Vibriobactin是一種由霍亂弧菌分泌且吸收的鐵載體。在本研究中，我們利用固相合成法合成vibriobactin，以省去大量合成與純化步驟。我們另外探討利用固相合成法與傳統的有機合成法製備vibriobactin－螢光基團共軛物的可行性，期望此共軛物可以選擇性地以螢光標記霍亂弧菌。 雙重抗生素共軛物被設想為解決嚴重的抗生素抗藥性的利器。MccJ25以及市售的rifampicin都是與RNA聚合酶結合的抗生素，而我們假設MccJ25-rifampicin共軛物具有協同效應，因此是更有效殺死細菌的抗生素。在本研究中，我們利用化學與生物方法製備MccJ25，炔基修飾的rifampicin，以及五乙二醇連接基團。這些建構單元將會被用於合成MccJ25-rifampicin共軛物，並探討其抑菌活性。

In chemical biology, conjugation refers to connecting two bioactive molecules into one molecule. In this thesis, we focus on preparing two kinds of conjugated compounds: a siderophore-fluorophore conjugate and a dual-antibiotic conjugate. Siderophores are a family of secondary metabolites secreted by bacteria under iron deficient conditions. Because microorganisms usually have highly selective receptors for the siderophore they produce, siderophores have been conjugated to various molecules, such as antibiotics and fluorophores, for a wide range of application. Vibriobactin is a siderophore produced, secreted, and retrieved by Vibrio cholerae. Here we investigated the on-resin synthesis of vibriobactin, with the goal of simplifying synthetic and purification efforts. Additionally, we explored both on-resin and in-solution synthesis of the vibriobactin-fluorophore conjugate, which could potentially serve as Vibrio cholerae specific fluorescent probe. To address the severe antibiotics resistance problem in clinical settings, dual-antibiotic conjugate has been proposed. Both MccJ25 and rifampicin are antibiotics that bind to RNAP, and we proposed that a MccJ25-rifampicin conjugate may exhibit synergistic effect and act as a more effective antibiotics. We utilize both biological and chemical approach to prepare MccJ25, alkyne-modified rifampicin, and pentaethylene glycol linker. These building blocks will be used to synthesized the MccJ25-rifampicin conjugate and evaluate its antibiotic activities.