7RWI

Mycobacterium tuberculosis RNA polymerase sigma L holoenzyme open promoter complex containing TNP-2198

Summary for 7RWI

• Entry DOI: 10.2210/pdb7rwi/pdb
• Descriptor: DNA-directed RNA polymerase subunit alpha, DNA-directed RNA polymerase subunit beta, DNA-directed RNA polymerase subunit beta', ... (8 entities in total)
• Functional Keywords: mycobacterium tuberculosis, rna polymerase, transcription inhibitor, tnp-2198, open promoter complex, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 8
• Total formula weight: 400329.70

Authors

Molodtsov, V.,Ebright, R.H. (deposition date: 2021-08-19, release date: 2022-03-02, Last modification date: 2023-10-18)

Primary citation

Ma, Z.,He, S.,Yuan, Y.,Zhuang, Z.,Liu, Y.,Wang, H.,Chen, J.,Xu, X.,Ding, C.,Molodtsov, V.,Lin, W.,Robertson, G.T.,Weiss, W.J.,Pulse, M.,Nguyen, P.,Duncan, L.,Doyle, T.,Ebright, R.H.,Lynch, A.S.
Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens.
J.Med.Chem., 65:4481-4495, 2022

PubMed Abstract: 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 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 infection, infection, and bacterial vaginosis.

PubMed: 35175750
DOI: 10.1021/acs.jmedchem.1c02045

Experimental method

X-RAY DIFFRACTION (3.7 Å)