Song Xiaojun, Lv Jianming, Cao Zhiqin, Huang Huiyun, Chen Guodong, Awakawa Takayoshi, Hu Dan, Gao Hao, Abe Ikuro, Yao Xinsheng
College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China.
Acta Pharm Sin B. 2021 Jun;11(6):1676-1685. doi: 10.1016/j.apsb.2020.12.007. Epub 2020 Dec 15.
Fusidane-type antibiotics, represented by helvolic acid, fusidic acid and cephalosporin P, are fungi-derived antimicrobials with little cross-resistance to commonly used antibiotics. Generation of new fusidane-type derivatives is therefore of great value, but this is hindered by available approaches. Here, we developed a stochastic combinational strategy by random assembly of all the post-tailoring genes derived from helvolic acid, fusidic acid, and cephalosporin P biosynthetic pathways in a strain that produces their common intermediate. Among a total of 27 gene combinations, 24 combinations produce expected products and afford 58 fusidane-type analogues, of which 54 are new compounds. Moreover, random gene combination can induce unexpected activity of some post-tailoring enzymes, leading to a further increase in chemical diversity. These newly generated derivatives provide new insights into the structure‒activity relationship of fusidane-type antibiotics. The stochastic combinational strategy established in this study proves to be a powerful approach for expanding structural diversity of natural products.
以蜂窝酸、夫西地酸和头孢菌素P为代表的夫西烷型抗生素是真菌衍生的抗菌剂，与常用抗生素几乎没有交叉耐药性。因此，新型夫西烷型衍生物的产生具有重要价值，但现有方法阻碍了这一过程。在此，我们通过将源自蜂窝酸、夫西地酸和头孢菌素P生物合成途径的所有后修饰基因随机组装到一个产生它们共同中间体的菌株中，开发了一种随机组合策略。在总共27种基因组合中，24种组合产生了预期产物，并提供了58种夫西烷型类似物，其中54种是新化合物。此外，随机基因组合可以诱导一些后修饰酶产生意想不到的活性，从而进一步增加化学多样性。这些新产生的衍生物为夫西烷型抗生素的构效关系提供了新的见解。本研究建立的随机组合策略被证明是一种扩展天然产物结构多样性的有效方法。
