Identification of Chemical Scaffolds That Inhibit the <i>Mycobacterium tuberculosis</i> Respiratory Complex Succinate Dehydrogenase
Drug-resistant <i>Mycobacterium tuberculosis</i> is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in <i>M. tuberculosis</i> under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in <i>M. tuberculosis</i>, we utilized a combination of biochemical screening and in-silico deep learning technologies to identify multiple chemical scaffolds capable of inhibiting mycobacterial SDH activity. Antimicrobial susceptibility assays show that lead inhibitors are bacteriostatic agents with activity against wild-type and drug-resistant strains of <i>M. tuberculosis</i>. Mode of action studies on lead compounds demonstrate that the specific inhibition of SDH activity dysregulates mycobacterial metabolism and respiration and results in the secretion of intracellular succinate. Interaction assays demonstrate that the chemical inhibition of SDH activity potentiates the activity of other bioenergetic inhibitors and prevents the emergence of resistance to a variety of drugs. Overall, this study shows that SDH inhibitors are promising next-generation antimicrobials against <i>M. tuberculosis</i>.
Authors
- Kiel Hards (ORCID: https://orcid.org/0000-0002-7887-4977)
- Zoe C. Williams
- Chen‐Yi Cheung (ORCID: https://orcid.org/0000-0002-5850-0919)
- Margaret Anne Brimble (ORCID: https://orcid.org/0000-0002-7086-4096)
- Gregory Murray Cook (ORCID: https://orcid.org/0000-0001-8349-1500)
- D.K. Inaoka (ORCID: https://orcid.org/0000-0002-9791-927X)
- Cara Adolph (ORCID: https://orcid.org/0000-0002-5020-9748)
- Laura M. Keighley
- Zhengqiu Li (ORCID: https://orcid.org/0000-0002-0433-2147)
- Anthony J. Hickey
- Jared S. Mackenzie (ORCID: https://orcid.org/0000-0002-3089-0900)
- Kiyoshi Kita (ORCID: https://orcid.org/0000-0002-0426-4308)
- Adrie J. C. Steyn (ORCID: https://orcid.org/0000-0001-9177-8827)
- Ming Yan (ORCID: https://orcid.org/0000-0001-9888-0744)
- Guo‐Bao Tian (ORCID: https://orcid.org/0000-0001-6750-5482)
- William J Jowsey (ORCID: https://orcid.org/0000-0002-7374-9675)
- Matthew B. McNeil (ORCID: https://orcid.org/0000-0001-7747-7745)
- Daniel P. Furkert (ORCID: https://orcid.org/0000-0001-6286-9105)
- Matson Kyte
- Tianyu Zhang (ORCID: https://orcid.org/0000-0001-5647-6014)
- Xiaobo Ding
Institutions
- University of Auckland (NZ)
- Sun Yat-sen University (CN)
- Jinan University (CN)
- Chinese Academy of Sciences (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- University of Alabama at Birmingham (US)
- Africa Health Research Institute (ZA)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Maurice Wilkins Centre (NZ)
- State Key Laboratory of Respiratory Disease (CN)
- University of Chinese Academy of Sciences (CN)
- Nagasaki University (JP)
- The University of Tokyo (JP)
- University of Otago (NZ)
- University of KwaZulu-Natal (ZA)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1021/acsinfecdis.3c00655
- Citations
- 5
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 1.95
Funders
- National Natural Science Foundation of China
- Maurice Wilkins Centre for Molecular Biodiscovery
- Health Research Council of New Zealand