药效团
化学
硝基咪唑
利福霉素
微生物学
立体化学
生物化学
抗生素
生物
有机化学
作者
Zhenkun Ma,Shijie He,Ying Yuan,Zhijun Zhuang,Yu Liu,Huan Wang,Jing Chen,Xiangyi Xu,Charles Z. Ding,Vadim Molodtsov,Wei Lin,Gregory T. Robertson,Jason Weiss,Mark Pulse,Phung M. Nguyen,Leonard R Duncan,Timothy B Doyle,Richard H. Ebright,A. Simon Lynch
标识
DOI:10.1021/acs.jmedchem.1c02045
摘要
TNP-2198, a stable conjugate of a rifamycin pharmacophore and a nitroimidazole pharmacophore, has been designed, synthesized, and evaluated as a novel dual-targeted antibacterial agent for the treatment of microaerophilic and anaerobic bacterial infections. TNP-2198 exhibits greater activity than a 1:1 molar mixture of the parent drugs and exhibits activity against strains resistant to both rifamycins and nitroimidazoles. A crystal structure of TNP-2198 bound to a Mycobacterium tuberculosis RNA polymerase transcription initiation complex reveals that the rifamycin portion of TNP-2198 binds to the rifamycin binding site on RNAP and the nitroimidazole portion of TNP-2198 interacts directly with the DNA template-strand in the RNAP active-center cleft, forming a hydrogen bond with a base of the DNA template strand. TNP-2198 is currently in Phase 2 clinical development for the treatment of Helicobacter pylori infection, Clostridioides difficile infection, and bacterial vaginosis.
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