TY - JOUR
T1 - Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens
AU - Ma, Zhenkun
AU - He, Shijie
AU - Yuan, Ying
AU - Zhuang, Zhijun
AU - Liu, Yu
AU - Wang, Huan
AU - Chen, Jing
AU - Xu, Xiangyi
AU - Ding, Charles
AU - Molodtsov, Vadim
AU - Lin, Wei
AU - Robertson, Gregory T.
AU - Weiss, William J.
AU - Pulse, Mark
AU - Nguyen, Phung
AU - Duncan, Leonard
AU - Doyle, Timothy
AU - Ebright, Richard H.
AU - Lynch, Anthony Simon
N1 - Funding Information:
The authors would like to thank the National Science and Technology Project of China (grant no. 2019ZX09721-001-004-008) for partial financial support of the work presented in this manuscript. For structural biology studies reported herein, we thank the Stanford Synchrotron Radiation Lightsource for beamline access. The structural biology work was supported by National Institutes of Health grant GM041376 to R.H.E. The authors thank current and past colleagues, academic collaborators, and supporting Contract Research Organizations for their respective contributions.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/3/24
Y1 - 2022/3/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85125287894&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c02045
DO - 10.1021/acs.jmedchem.1c02045
M3 - Article
C2 - 35175750
AN - SCOPUS:85125287894
SN - 0022-2623
VL - 65
SP - 4481
EP - 4495
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -