台灣本土真菌 Neosartorya fischeri 之二次代謝物之化學結構及生物活性分析

Abstract

自抗生素被發現並引進現代醫學以後，在醫療中一直扮演著舉足輕重的角色。然而，抗生素不同於其他的藥物，由於細菌的迅速演化，在長時間的抗生素使用之下，抗藥性致病菌不停的增加，而大大的減少了可以運用的抗生素選項。例如，具有多重抗藥性的抗甲氧西林金黃色葡萄球菌（MRSA）已是常見的院內感染菌株。抗藥性菌株的出現已經成為現代醫學的最大的挑戰之一，因此尋找新一代抗生素以對抗細菌感染已經是一個刻不容緩的課題。由於天然物具備高度的結構複雜性，並且在演化的過程之下產生許多生物活性，故天然物一直以來都是重要的新藥來源。 在本研究中，我們發現一株來自花蓮縣的本土土壤真菌Neosartorya fischeri分泌的二次代謝物具有抑制細菌生長的活性。利用以活性為導向的策略，將真菌培養並以有機溶劑萃取，經過層析方法（粒徑篩析及矽膠開放式管柱層析、高效液相層析儀）純化且分離出純物質，並使用光譜學方法（核磁共振光譜、紅外光吸收光譜、高解析電噴灑游離質譜）鑑定其化學結構。此外，也利用生物實驗測試其生物活性。最後，在本研究中描述二個二萜類（diterpenoid）化合物sartorypyrone A 及 aszonapyrone A、一個吲哚生物鹼（indole alkaloid）acetylaszonalenin、及兩個具有甲醯胺基（N-formyl group）的新生物鹼。其中，二萜類1號化合物sartorypyrone A衍生物具有最好的生物活性，具備抑制格蘭氏陽性菌生長的能力，甚至對於抗甲氧西林金黃色葡萄球菌（MRSA）也具有很好的抑制效果。另外，也兼具有抗癌細胞活性。因此，我們相信其具有用於新藥開發的潛力。

Ever since antibiotics were discovered and introduced into modern medicine, they have played a pivotal role in the improvement of public health. However, unlike other frequently prescribed drugs, antibiotics tend to gradually lose their efficacy due to the evolution of drug-resistant bacteria. The emergence of multi-drug resistance has become one of the major threats to global healthcare; therefore, finding novel antibiotics has become a critical key to fight against bacterial infections. Since natural products are rich in structural diversity and are evolutionarily produced to be drug alike, they remain important sources of potential drug leads. Here, several secondary metabolites were isolated from an indigenous fungal species, Neosartorya fischeri, collected from soil in Hualien, Taiwan. The fungus was cultured, then its secondary metabolites were extracted and purified with chromatographic techniques (Size-exclusion and silica gel OPC, HPLC) to obtain pure compounds. All chemical structures were elucidated using spectroscopic methods (NMR, FTIR, HR-ESI-MS). Moreover, bioassays were conducted to evaluate their bioactivities. Two diterpenoids sartorypyrone A and aszonapyrone A, one indole alkaloid acetylaszonalenin, and two novel N-formyl alkaloids were reported in this study. Among the compounds being identified thus far, compound 1, sartorypyrone A, showed the best antimicrobial activities against Gram-positive bacteria and even against Methicillin-resistant Staphylococcus aureus (MRSA). In addition, it also showed anticancer activity. Therefore, we believe it can be a potential lead compound for drug development.