A dual-targeting succinate dehydrogenase and F1Fo-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

Cara Adolph; Chen-Yi Cheung; Matthew B. McNeil; William J. Jowsey; Zoe C. Williams; Kiel Hards; Liam K. Harold; Ashraf Aboelela; Richard S. Bujaroski; Benjamin J. Buckley; Joel D. A. Tyndall; Zhengqiu Li; Julian D. Langer; Laura Preiss; Thomas Meier; Adrie J. C. Steyn; Kyu Y. Rhee; Michael Berney; Michael J. Kelso; Gregory M. Cook

doi:10.1016/j.chembiol.2023.12.002

A dual-targeting succinate dehydrogenase and F₁F_o-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

Cara Adolph, Chen-Yi Cheung, Matthew B. McNeil, William J. Jowsey, Zoe C. Williams, Kiel Hards, Liam K. Harold, Ashraf Aboelela, Richard S. Bujaroski, Benjamin J. Buckley, Joel D. A. Tyndall, Zhengqiu Li, Julian D. Langer, Laura Preiss, Thomas Meier, Adrie J. C. Steyn, Kyu Y. Rhee, Michael Berney, Michael J. Kelso, Gregory M. Cook^*

^*Corresponding author for this work

School of Medicine

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

Abstract

Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the F₁F_o-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M. tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M. tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.

Original language	English
Pages (from-to)	683-698.e7
Number of pages	23
Journal	Cell Chemical Biology
Volume	31
Issue number	4
Early online date	26 Dec 2023
DOIs	https://doi.org/10.1016/j.chembiol.2023.12.002
Publication status	Published - 18 Apr 2024

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10.1016/j.chembiol.2023.12.002

Cite this

Adolph, C., Cheung, C.-Y., McNeil, M. B., Jowsey, W. J., Williams, Z. C., Hards, K., Harold, L. K., Aboelela, A., Bujaroski, R. S., Buckley, B. J., Tyndall, J. D. A., Li, Z., Langer, J. D., Preiss, L., Meier, T., Steyn, A. J. C., Rhee, K. Y., Berney, M., Kelso, M. J., & Cook, G. M. (2024). A dual-targeting succinate dehydrogenase and F₁F_o-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis. Cell Chemical Biology, 31(4), 683-698.e7. https://doi.org/10.1016/j.chembiol.2023.12.002

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title = "A dual-targeting succinate dehydrogenase and F1Fo-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis",

abstract = "Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the F1Fo-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M. tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M. tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.",

author = "Cara Adolph and Chen-Yi Cheung and McNeil, \{Matthew B.\} and Jowsey, \{William J.\} and Williams, \{Zoe C.\} and Kiel Hards and Harold, \{Liam K.\} and Ashraf Aboelela and Bujaroski, \{Richard S.\} and Buckley, \{Benjamin J.\} and Tyndall, \{Joel D. A.\} and Zhengqiu Li and Langer, \{Julian D.\} and Laura Preiss and Thomas Meier and Steyn, \{Adrie J. C.\} and Rhee, \{Kyu Y.\} and Michael Berney and Kelso, \{Michael J.\} and Cook, \{Gregory M.\}",

note = "Funding:This work was financially supported by the Health Research Council of New Zealand, the Maurice Wilkins Centre (MWC) for Molecular Biodiscovery, and the China-MWC Biomedical Collaboration Fund. In addition, this research was funded in part by the Wellcome Trust [WT110068/Z/15/Z] to T.M. and the NIAID R01AI137043 grant to A.J.C.S.",

year = "2024",

month = apr,

day = "18",

doi = "10.1016/j.chembiol.2023.12.002",

language = "English",

volume = "31",

pages = "683--698.e7",

journal = "Cell Chemical Biology",

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Adolph, C, Cheung, C-Y, McNeil, MB, Jowsey, WJ, Williams, ZC, Hards, K, Harold, LK, Aboelela, A, Bujaroski, RS, Buckley, BJ, Tyndall, JDA, Li, Z, Langer, JD, Preiss, L, Meier, T, Steyn, AJC, Rhee, KY, Berney, M, Kelso, MJ & Cook, GM 2024, 'A dual-targeting succinate dehydrogenase and F₁F_o-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis', Cell Chemical Biology, vol. 31, no. 4, pp. 683-698.e7. https://doi.org/10.1016/j.chembiol.2023.12.002

TY - JOUR

T1 - A dual-targeting succinate dehydrogenase and F1Fo-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

AU - Adolph, Cara

AU - Cheung, Chen-Yi

AU - McNeil, Matthew B.

AU - Jowsey, William J.

AU - Williams, Zoe C.

AU - Hards, Kiel

AU - Harold, Liam K.

AU - Aboelela, Ashraf

AU - Bujaroski, Richard S.

AU - Buckley, Benjamin J.

AU - Tyndall, Joel D. A.

AU - Li, Zhengqiu

AU - Langer, Julian D.

AU - Preiss, Laura

AU - Meier, Thomas

AU - Steyn, Adrie J. C.

AU - Rhee, Kyu Y.

AU - Berney, Michael

AU - Kelso, Michael J.

AU - Cook, Gregory M.

N1 - Funding:This work was financially supported by the Health Research Council of New Zealand, the Maurice Wilkins Centre (MWC) for Molecular Biodiscovery, and the China-MWC Biomedical Collaboration Fund. In addition, this research was funded in part by the Wellcome Trust [WT110068/Z/15/Z] to T.M. and the NIAID R01AI137043 grant to A.J.C.S.

PY - 2024/4/18

Y1 - 2024/4/18

N2 - Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the F1Fo-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M. tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M. tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.

AB - Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the F1Fo-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M. tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M. tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.

U2 - 10.1016/j.chembiol.2023.12.002

DO - 10.1016/j.chembiol.2023.12.002

M3 - Article

C2 - 38151019

SN - 2451-9456

VL - 31

SP - 683-698.e7

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 4