Author: Cheung, Chen-Yi ; Steyn, Adrie J.C. ; Hards, Kiel ; Kita, Kiyoshi ; Yan, Ming ; Jowsey, William J. ; Mackenzie, Jared S. ; Hickey, Anthony J.R. ; Ding, Xiaobo ; Li, Zhengqiu ; Furkert, Daniel P. ; Williams, Zoe C. ; Cook, Gregory M. ; Adolph, Cara ; McNeil, Matthew B. ; Zhang, Tianyu ; Keighley, Laura M. ; Inaoka, Daniel Ken ; Brimble, Margaret A. ; Kyte, Matson ; Tian, Guo-Bao

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.

01 Jan 2024·Current Research in Biotechnology

Unveiling the antimicrobial action of MMV676501, MMV687807, and MMV102872 against Staphylococcus aureus: A mechanistic investigation

Author: Brahma, Umarani ; Bhandari, Vasundhra ; Suresh, Akash ; Sharma, Paresh

The urgent need for new antimicrobials combats the rising threat of resistant pathogens.To optimize lead compounds, understanding their mechanisms of action is crucial for target optimization and improved pharmacokinetics.We employed microarray anal. to investigate the impact of selected MMV compounds on the S. aureus transcriptome.Differential gene expression (DEG) anal. was performed following exposure to MMV 676501, MMV 687807, and MMV 102872.MMV 676501 treatment resulted in 26 DEGs (12 upregulated, 14 downregulated).Similarly, MMV 687807 and MMV 102872 treatments yielded 34 DEGs (11 upregulated, 23 downregulated) and 31 DEGs (18 upregulated, 13 downregulated), resp.Pathway anal. revealed that MMV 676501 targets nitrogen metabolism, while MMV 102872 downregulates genes (purS, purC, lexA) involved in purine metabolismMMV 687807 appears to affect multiple metabolic pathways.Our transcriptomic approach demonstrates the differential impact of MMV compounds on S. aureus.These results provide mechanistic insights, highlighting specific metabolic pathways affected by each compoundThis knowledge is valuable for guiding future target optimization and improving the compounds pharmacol. properties.

01 May 2023·European Journal of Medicinal Chemistry

Identification and characterisation of the tegument-expressed aldehyde dehydrogenase SmALDH_312 of Schistosoma mansoni, a target of disulfiram

Article

Author: Ueberall, Monique E ; Schlitzer, Martin ; Gallinger, Tom L ; Falcone, Franco H ; Harnischfeger, Julie ; Haeberlein, Simone ; Becker, Katja ; Timm, Thomas ; Quack, Thomas ; Rennar, Georg A ; Blohm, Ariane ; Salzig, Denise ; Beutler, Mandy ; Lochnit, Günter ; Houhou, Hicham ; Grevelding, Christoph G ; Czermak, Peter ; Rahlfs, Stefan ; Hahnel, Steffen R ; Weber, Michael H W

Schistosomiasis is an infectious disease caused by blood flukes of the genus Schistosoma and affects approximately 200 million people worldwide. Since Praziquantel (PZQ) is the only drug for schistosomiasis, alternatives are needed. By a biochemical approach, we identified a tegumentally expressed aldehyde dehydrogenase (ALDH) of S. mansoni, SmALDH_312. Molecular analyses of adult parasites showed Smaldh_312 transcripts in both genders and different tissues. Physiological and cell-biological experiments exhibited detrimental effects of the drug disulfiram (DSF), a known ALDH inhibitor, on larval and adult schistosomes in vitro. DSF also reduced stem-cell proliferation and caused severe tegument damage in treated worms. In silico-modelling of SmALDH_312 and docking analyses predicted DSF binding, which we finally confirmed by enzyme assays with recombinant SmALDH_312. Furthermore, we identified compounds of the Medicine for Malaria Venture (MMV) pathogen box inhibiting SmALDH_312 activity. Our findings represent a promising starting point for further development towards new drugs for schistosomiasis.

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Indication	Highest Phase	Country/Location	Organization	Date
Candidiasis	Preclinical	United States	MMV Medicines for Malaria Venture	27 Dec 2016

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