J Biol Chem. 2014 Jul 25;289(30):21142-52. doi: 10.1074/jbc.M114.572636.
Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy, and AIDS-related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin-resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase domain of module 6 of rifamycin polyketide synthase with that of module 2 of rapamycin polyketide synthase. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-Desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains.
利福霉素 B 是地中海诺卡氏菌 S699 的产物，是临床用于治疗结核病、麻风病和艾滋病相关分枝杆菌感染的有效抗生素的前体。然而，这些抗生素的长期使用导致了结核分枝杆菌利福霉素耐药株的出现。作为我们努力生成更好的利福霉素类似物的一部分，我们用雷帕霉素聚酮合酶的模块 2 的酰基转移酶结构域取代了利福霉素聚酮合酶的模块 6 的酰基转移酶结构域。由此产生的地中海诺卡氏菌 S699 的突变体（rifAT6::rapAT2）产生了新的利福霉素类似物 24-去甲基利福霉素 B 和 24-去甲基利福霉素 SV，它们在聚酮骨架中含有修饰。然后将 24-去甲基利福霉素 B 转化为 24-去甲基利福霉素 S，其结构通过 MS、NMR 和 X 射线晶体学得到确认。随后，将 24-去甲基利福霉素 S 转化为 24-去甲基利福霉素，它对几种耐利福平的结核分枝杆菌菌株表现出优异的抗菌活性。
