Cara Adolph, Kiel Hards, Zoe C. Williams, Chen-Yi Cheung, Laura M. Keighley, William J. Jowsey, Matson Kyte, Daniel Ken Inaoka, Kiyoshi Kita, Jared S. Mackenzie, Adrie J.C. Steyn, Zhengqiu Li, Ming Yan, Guo-Bao Tian, Tianyu Zhang, Xiaobo Ding, Daniel P. Furkert, Margaret A. Brimble, Anthony J.R. Hickey, Matthew B. McNeil, Gregory M. Cook
{"title":"鉴定抑制结核分枝杆菌呼吸复合体琥珀酸脱氢酶的化学支架","authors":"Cara Adolph, Kiel Hards, Zoe C. Williams, Chen-Yi Cheung, Laura M. Keighley, William J. Jowsey, Matson Kyte, Daniel Ken Inaoka, Kiyoshi Kita, Jared S. Mackenzie, Adrie J.C. Steyn, Zhengqiu Li, Ming Yan, Guo-Bao Tian, Tianyu Zhang, Xiaobo Ding, Daniel P. Furkert, Margaret A. Brimble, Anthony J.R. Hickey, Matthew B. McNeil, Gregory M. Cook","doi":"10.1021/acsinfecdis.3c00655","DOIUrl":null,"url":null,"abstract":"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>.","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":null,"pages":null},"PeriodicalIF":8.3000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase\",\"authors\":\"Cara Adolph, Kiel Hards, Zoe C. Williams, Chen-Yi Cheung, Laura M. Keighley, William J. Jowsey, Matson Kyte, Daniel Ken Inaoka, Kiyoshi Kita, Jared S. Mackenzie, Adrie J.C. 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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. 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Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase
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.
期刊介绍:
ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.