Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase.

Autor: Adolph C; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand., Hards K; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand., Williams ZC; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.; Africa Health Research Institute, University of KwaZulu Natal, Durban 4001, South Africa., Cheung CY; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand., Keighley LM; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand., Jowsey WJ; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand., Kyte M; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand., Inaoka DK; School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan.; Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.; Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan., Kita K; School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan.; Department of Host-Defence Biochemistry, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan., Mackenzie JS; Africa Health Research Institute, University of KwaZulu Natal, Durban 4001, South Africa., Steyn AJC; Africa Health Research Institute, University of KwaZulu Natal, Durban 4001, South Africa.; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.; Centres for AIDS Research and Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States., Li Z; School of Pharmacy, Jinan University, Guangzhou 510632, China., Yan M; School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China., Tian GB; Department of Immunology, School of Medicine, Sun Yat-Sen University, Shenzhen 518107, China.; Advanced Medical Technology Centre, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.; Key Laboratory of Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, China., Zhang T; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.; University of Chinese Academy of Sciences, Beijing 100049, China.; Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China., Ding X; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand.; School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand., Furkert DP; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand.; School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand., Brimble MA; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand.; School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand.; School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand., Hickey AJR; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand.; School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand., McNeil MB; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand., Cook GM; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand.; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2024 Oct 11; Vol. 10 (10), pp. 3496-3515. Date of Electronic Publication: 2024 Sep 13.
DOI: 10.1021/acsinfecdis.3c00655
Abstrakt: Drug-resistant Mycobacterium tuberculosis 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 M. tuberculosis under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in M. tuberculosis , 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 M. tuberculosis . 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 M. tuberculosis .
Databáze: MEDLINE