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 |
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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 | |
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