Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly

Yixin Cui; Alice Lanne; Xudan Peng; Edward Browne; Apoorva Bhatt; Nicholas J. Coltman; Philip Craven; Liam R. Cox; Nicholas J. Cundy; Katie Dale; Antonio Feula; Jon Frampton; Martin Fung; Michael Morton; Aaron Goff; Mariwan Salih; Xingfen Lang; Xingjian Li; Chris Moon; Jordan Pascoe; Vanessa Portman; Cara Press; Timothy Schulz-Utermoehl; Suki Lee; Micky D. Tortorella; Zhengchao Tu; Zoe E. Underwood; Changwei Wang; Akina Yoshizawa; Tianyu Zhang; Simon J. Waddell; Joanna Bacon; Luke Alderwick; John S. Fossey; Cleopatra Neagoie

doi:10.1021/acs.jmedchem.3c01643

Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly

Yixin Cui, Alice Lanne, Xudan Peng, Edward Browne, Apoorva Bhatt, Nicholas J. Coltman, Philip Craven, Liam R. Cox, Nicholas J. Cundy, Katie Dale, Antonio Feula, Jon Frampton, Martin Fung, Michael Morton, Aaron Goff, Mariwan Salih, Xingfen Lang, Xingjian Li, Chris Moon, Jordan PascoeVanessa Portman, Cara Press, Timothy Schulz-Utermoehl, Suki Lee, Micky D. Tortorella, Zhengchao Tu, Zoe E. Underwood, Changwei Wang, Akina Yoshizawa, Tianyu Zhang, Simon J. Waddell, Joanna Bacon, Luke Alderwick^*, John S. Fossey^*, Cleopatra Neagoie^*

^*Corresponding author for this work

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Abstract

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC₉₉ values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies.

Original language	English
Pages (from-to)	2529-2548
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	67
Issue number	4
Early online date	8 Feb 2024
DOIs	https://doi.org/10.1021/acs.jmedchem.3c01643
Publication status	Published - 22 Feb 2024

Bibliographical note

Acknowledgments:
We dedicate this study to the memory of Professor John Fossey, an exceptional synthetic chemist who passed away on April 15, 2022. Professor Fossey’s passion for chirality and stereoselective synthesis marked him as a distinguished scientific leader in the field of chemistry. His legacy endures through his scientific integrity, innovative thinking, and his role as a remarkable scientific mentor and collaborator. Professor John Fossey will be profoundly missed by colleagues, family, and friends, and we extend our deepest sympathies and sincere condolences to his loved ones. We are grateful for the support underpinning much of this study from MRC Confidence in Concepts and EPSRC follow-on fund schemes. The University of Birmingham is acknowledged for support, including travel funds permitting A.Y., X.L., and Y.C. to undertake training placements at GIBH. J.S.F. is grateful to the Royal Society for the training provided because of a previous Industrial Fellowship and the EPSRC for previous funding (EP/J003220/1). Funding for part of this study was received from Public Health England. This work was supported by the National Key R&D Program of China (2021 YFA1300900) and by the Chinese Academy of Sciences Grant (YJKYYQ20210026, 154144KYSB20190005). S.J.W. and A.G. thank the National Centre for the Replacement, Refinement. and Reduction of Animals in Research (NC3Rs) for grant support (NC/R001669/1). Qiong Pan (GIBH), Jingfang Xiong (GIBH). and Miaoqin She (GIBH) are acknowledged for conducting aspects of the PK/PD studies of this report. Dr. Chi Tsang (UoB), Dr. Peter Ashton (UoB), and Jiajia Wei (GIBH) are acknowledged for their helpful discussions and practical support with aspects of mass spectrometry. Dr. Cécile S. Le Duff (UoB) and Dr. Neil Spencer (UoB) gave advice on aspects of NMR spectroscopy underpinning the preliminary or previously reported, findings. Yingxue Liu (GIBH) is acknowledged for help with the purification of final products by HPLC where required.

Keywords

Humans
Mycobacterium tuberculosis
Azetidines/pharmacology
Antitubercular Agents/pharmacology
Tuberculosis, Multidrug-Resistant/drug therapy
Extensively Drug-Resistant Tuberculosis/drug therapy
Microbial Sensitivity Tests

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cui, Y., Lanne, A., Peng, X., Browne, E., Bhatt, A., Coltman, N. J., Craven, P., Cox, L. R., Cundy, N. J., Dale, K., Feula, A., Frampton, J., Fung, M., Morton, M., Goff, A., Salih, M., Lang, X., Li, X., Moon, C., ... Neagoie, C. (2024). Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly. Journal of Medicinal Chemistry, 67(4), 2529-2548. https://doi.org/10.1021/acs.jmedchem.3c01643

@article{d75f2e651db041aba7e0c44cba6b9839,

title = "Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly",

abstract = "Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies. ",

keywords = "Humans, Mycobacterium tuberculosis, Azetidines/pharmacology, Antitubercular Agents/pharmacology, Tuberculosis, Multidrug-Resistant/drug therapy, Extensively Drug-Resistant Tuberculosis/drug therapy, Microbial Sensitivity Tests",

author = "Yixin Cui and Alice Lanne and Xudan Peng and Edward Browne and Apoorva Bhatt and Coltman, {Nicholas J.} and Philip Craven and Cox, {Liam R.} and Cundy, {Nicholas J.} and Katie Dale and Antonio Feula and Jon Frampton and Martin Fung and Michael Morton and Aaron Goff and Mariwan Salih and Xingfen Lang and Xingjian Li and Chris Moon and Jordan Pascoe and Vanessa Portman and Cara Press and Timothy Schulz-Utermoehl and Suki Lee and Tortorella, {Micky D.} and Zhengchao Tu and Underwood, {Zoe E.} and Changwei Wang and Akina Yoshizawa and Tianyu Zhang and Waddell, {Simon J.} and Joanna Bacon and Luke Alderwick and Fossey, {John S.} and Cleopatra Neagoie",

note = "Acknowledgments: We dedicate this study to the memory of Professor John Fossey, an exceptional synthetic chemist who passed away on April 15, 2022. Professor Fossey{\textquoteright}s passion for chirality and stereoselective synthesis marked him as a distinguished scientific leader in the field of chemistry. His legacy endures through his scientific integrity, innovative thinking, and his role as a remarkable scientific mentor and collaborator. Professor John Fossey will be profoundly missed by colleagues, family, and friends, and we extend our deepest sympathies and sincere condolences to his loved ones. We are grateful for the support underpinning much of this study from MRC Confidence in Concepts and EPSRC follow-on fund schemes. The University of Birmingham is acknowledged for support, including travel funds permitting A.Y., X.L., and Y.C. to undertake training placements at GIBH. J.S.F. is grateful to the Royal Society for the training provided because of a previous Industrial Fellowship and the EPSRC for previous funding (EP/J003220/1). Funding for part of this study was received from Public Health England. This work was supported by the National Key R&D Program of China (2021 YFA1300900) and by the Chinese Academy of Sciences Grant (YJKYYQ20210026, 154144KYSB20190005). S.J.W. and A.G. thank the National Centre for the Replacement, Refinement. and Reduction of Animals in Research (NC3Rs) for grant support (NC/R001669/1). Qiong Pan (GIBH), Jingfang Xiong (GIBH). and Miaoqin She (GIBH) are acknowledged for conducting aspects of the PK/PD studies of this report. Dr. Chi Tsang (UoB), Dr. Peter Ashton (UoB), and Jiajia Wei (GIBH) are acknowledged for their helpful discussions and practical support with aspects of mass spectrometry. Dr. C{\'e}cile S. Le Duff (UoB) and Dr. Neil Spencer (UoB) gave advice on aspects of NMR spectroscopy underpinning the preliminary or previously reported, findings. Yingxue Liu (GIBH) is acknowledged for help with the purification of final products by HPLC where required. ",

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doi = "10.1021/acs.jmedchem.3c01643",

language = "English",

volume = "67",

pages = "2529--2548",

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Cui, Y, Lanne, A, Peng, X, Browne, E, Bhatt, A, Coltman, NJ, Craven, P , Cox, LR, Cundy, NJ, Dale, K, Feula, A, Frampton, J, Fung, M, Morton, M, Goff, A, Salih, M, Lang, X, Li, X, Moon, C, Pascoe, J, Portman, V, Press, C, Schulz-Utermoehl, T, Lee, S, Tortorella, MD, Tu, Z, Underwood, ZE, Wang, C, Yoshizawa, A, Zhang, T, Waddell, SJ, Bacon, J, Alderwick, L, Fossey, JS & Neagoie, C 2024, 'Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly', Journal of Medicinal Chemistry, vol. 67, no. 4, pp. 2529-2548. https://doi.org/10.1021/acs.jmedchem.3c01643

TY - JOUR

T1 - Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly

AU - Cui, Yixin

AU - Lanne, Alice

AU - Peng, Xudan

AU - Browne, Edward

AU - Bhatt, Apoorva

AU - Coltman, Nicholas J.

AU - Craven, Philip

AU - Cox, Liam R.

AU - Cundy, Nicholas J.

AU - Dale, Katie

AU - Feula, Antonio

AU - Frampton, Jon

AU - Fung, Martin

AU - Morton, Michael

AU - Goff, Aaron

AU - Salih, Mariwan

AU - Lang, Xingfen

AU - Li, Xingjian

AU - Moon, Chris

AU - Pascoe, Jordan

AU - Portman, Vanessa

AU - Press, Cara

AU - Schulz-Utermoehl, Timothy

AU - Lee, Suki

AU - Tortorella, Micky D.

AU - Tu, Zhengchao

AU - Underwood, Zoe E.

AU - Wang, Changwei

AU - Yoshizawa, Akina

AU - Zhang, Tianyu

AU - Waddell, Simon J.

AU - Bacon, Joanna

AU - Alderwick, Luke

AU - Fossey, John S.

AU - Neagoie, Cleopatra

N1 - Acknowledgments: We dedicate this study to the memory of Professor John Fossey, an exceptional synthetic chemist who passed away on April 15, 2022. Professor Fossey’s passion for chirality and stereoselective synthesis marked him as a distinguished scientific leader in the field of chemistry. His legacy endures through his scientific integrity, innovative thinking, and his role as a remarkable scientific mentor and collaborator. Professor John Fossey will be profoundly missed by colleagues, family, and friends, and we extend our deepest sympathies and sincere condolences to his loved ones. We are grateful for the support underpinning much of this study from MRC Confidence in Concepts and EPSRC follow-on fund schemes. The University of Birmingham is acknowledged for support, including travel funds permitting A.Y., X.L., and Y.C. to undertake training placements at GIBH. J.S.F. is grateful to the Royal Society for the training provided because of a previous Industrial Fellowship and the EPSRC for previous funding (EP/J003220/1). Funding for part of this study was received from Public Health England. This work was supported by the National Key R&D Program of China (2021 YFA1300900) and by the Chinese Academy of Sciences Grant (YJKYYQ20210026, 154144KYSB20190005). S.J.W. and A.G. thank the National Centre for the Replacement, Refinement. and Reduction of Animals in Research (NC3Rs) for grant support (NC/R001669/1). Qiong Pan (GIBH), Jingfang Xiong (GIBH). and Miaoqin She (GIBH) are acknowledged for conducting aspects of the PK/PD studies of this report. Dr. Chi Tsang (UoB), Dr. Peter Ashton (UoB), and Jiajia Wei (GIBH) are acknowledged for their helpful discussions and practical support with aspects of mass spectrometry. Dr. Cécile S. Le Duff (UoB) and Dr. Neil Spencer (UoB) gave advice on aspects of NMR spectroscopy underpinning the preliminary or previously reported, findings. Yingxue Liu (GIBH) is acknowledged for help with the purification of final products by HPLC where required.

PY - 2024/2/22

Y1 - 2024/2/22

N2 - Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies.

AB - Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies.

KW - Humans

KW - Mycobacterium tuberculosis

KW - Azetidines/pharmacology

KW - Antitubercular Agents/pharmacology

KW - Tuberculosis, Multidrug-Resistant/drug therapy

KW - Extensively Drug-Resistant Tuberculosis/drug therapy

KW - Microbial Sensitivity Tests

U2 - 10.1021/acs.jmedchem.3c01643

DO - 10.1021/acs.jmedchem.3c01643

M3 - Article

C2 - 38331432

SN - 0022-2623

VL - 67

SP - 2529

EP - 2548

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 4

ER -

Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly

Abstract

Bibliographical note

Keywords

UN SDGs

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