Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens

Zhenkun Ma; Shijie He; Ying Yuan; Zhijun Zhuang; Yu Liu; Huan Wang; Jing Chen; Xiangyi Xu; Charles Ding; Vadim Molodtsov; Wei Lin; Gregory T. Robertson; William J. Weiss; Mark Pulse; Phung Nguyen; Leonard Duncan; Timothy Doyle; Richard H. Ebright; Anthony Simon Lynch

doi:10.1021/acs.jmedchem.1c02045

Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens

Zhenkun Ma, Shijie He, Ying Yuan, Zhijun Zhuang, Yu Liu, Huan Wang, Jing Chen, Xiangyi Xu, Charles Ding, Vadim Molodtsov, Wei Lin, Gregory T. Robertson, William J. Weiss, Mark Pulse, Phung Nguyen, Leonard Duncan, Timothy Doyle, Richard H. Ebright, Anthony Simon Lynch

Waksman Institute of Microbiology

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	American English
Pages (from-to)	4481-4495
Number of pages	15
Journal	Journal of medicinal chemistry
Volume	65
Issue number	6
DOIs	https://doi.org/10.1021/acs.jmedchem.1c02045
State	Published - Mar 24 2022

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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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. (2022). Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens. Journal of medicinal chemistry, 65(6), 4481-4495. https://doi.org/10.1021/acs.jmedchem.1c02045

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title = "Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens",

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 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.",

author = "Zhenkun Ma and Shijie He and Ying Yuan and Zhijun Zhuang and Yu Liu and Huan Wang and Jing Chen and Xiangyi Xu and Charles Ding and Vadim Molodtsov and Wei Lin and Robertson, {Gregory T.} and Weiss, {William J.} and Mark Pulse and Phung Nguyen and Leonard Duncan and Timothy Doyle and Ebright, {Richard H.} and Lynch, {Anthony Simon}",

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year = "2022",

month = mar,

day = "24",

doi = "10.1021/acs.jmedchem.1c02045",

language = "American English",

volume = "65",

pages = "4481--4495",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

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Ma, Z, He, S, Yuan, Y, Zhuang, Z, Liu, Y, Wang, H, Chen, J, Xu, X, Ding, C, Molodtsov, V, Lin, W, Robertson, GT, Weiss, WJ, Pulse, M, Nguyen, P, Duncan, L, Doyle, T, Ebright, RH & Lynch, AS 2022, 'Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens', Journal of medicinal chemistry, vol. 65, no. 6, pp. 4481-4495. https://doi.org/10.1021/acs.jmedchem.1c02045

Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens. / Ma, Zhenkun; He, Shijie; Yuan, Ying et al.
In: Journal of medicinal chemistry, Vol. 65, No. 6, 24.03.2022, p. 4481-4495.

Research output: Contribution to journal › Article › peer-review

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

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.

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U2 - 10.1021/acs.jmedchem.1c02045

DO - 10.1021/acs.jmedchem.1c02045

M3 - Article

C2 - 35175750

SN - 0022-2623

VL - 65

SP - 4481

EP - 4495

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 6

ER -

Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens

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