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Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus

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dc.contributor Háskóli Íslands
dc.contributor University of Iceland
dc.contributor.author Kulkarni, Amogh
dc.contributor.author Soni, Isha
dc.contributor.author Kelkar, Dhanashree S.
dc.contributor.author Dharmaraja, Allimuthu T.
dc.contributor.author Sankar, Rathinam K.
dc.contributor.author Beniwal, Gaurav
dc.contributor.author Rajendran, Abinaya
dc.contributor.author Tamhankar, Sharvari
dc.contributor.author Chopra, Sidharth
dc.contributor.author Kamat, Siddhesh S.
dc.contributor.author Chakrapani, Harinath
dc.date.accessioned 2020-03-30T15:49:51Z
dc.date.available 2020-03-30T15:49:51Z
dc.date.issued 2019-06-26
dc.identifier.citation Amogh Kulkarni, Isha Soni, Dhanashree S. Kelkar, Allimuthu T. Dharmaraja, Rathinam K. Sankar, Gaurav Beniwal, Abinaya Rajendran, Sharvari Tamhankar, Sidharth Chopra, Siddhesh S. Kamat, and Harinath Chakrapani Journal of Medicinal Chemistry 2019 62 (14), 6785-6795 DOI: 10.1021/acs.jmedchem.9b00774
dc.identifier.issn 0022-2623
dc.identifier.issn 1520-4804
dc.identifier.uri https://hdl.handle.net/20.500.11815/1674
dc.description Publisher's version (útgefin grein)
dc.description.abstract The alarming global rise in fatalities from multidrug-resistant Staphylococcus aureus (S. aureus) infections has underscored a need to develop new therapies to address this epidemic. Chemoproteomics is valuable in identifying targets for new drugs in different human diseases including bacterial infections. Targeting functional cysteines is particularly attractive, as they serve critical catalytic functions that enable bacterial survival. Here, we report an indole-based quinone epoxide scaffold with a unique boat-like conformation that allows steric control in modulating thiol reactivity. We extensively characterize a lead compound (4a), which potently inhibits clinically derived vancomycin-resistant S. aureus. Leveraging diverse chemoproteomic platforms, we identify and biochemically validate important transcriptional factors as potent targets of 4a. Interestingly, each identified transcriptional factor has a conserved catalytic cysteine residue that confers antibiotic tolerance to these bacteria. Thus, the chemical tools and biological targets that we describe here prospect new therapeutic paradigms in combatting S. aureus infections.
dc.description.sponsorship The authors thank the Department of Biotechnology (DBT), Government of India (BT/PR15848/MED/29/1025/2016 to H.C. and S.C.), a Wellcome Trust DBT India Alliance Intermediate Fellowship (IA/I/15/2/502058 to S.S.K.) and a DST-FIST Infrastructure Development Grant (to IISER Pune Biology) for the financial support for our research. The Council for Scientific and Industrial Research (CSIR) and the Department of Science and Technology—Innovation in Science Pursuit for Inspired Research (DST-INSPIRE) for graduate student fellowships.
dc.format.extent 6785-6795
dc.language.iso en
dc.publisher American Chemical Society (ACS)
dc.relation.ispartofseries Journal of Medicinal Chemistry;62(14)
dc.rights info:eu-repo/semantics/openAccess
dc.subject Molecular Medicine
dc.subject Drug Discovery
dc.subject Lyfjagerð
dc.subject Sameindafræði
dc.title Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus
dc.type info:eu-repo/semantics/article
dcterms.license This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
dc.description.version Peer Reviewed
dc.identifier.journal Journal of Medicinal Chemistry
dc.identifier.doi 10.1021/acs.jmedchem.9b00774
dc.contributor.department Lyfjafræðideild (HÍ)
dc.contributor.department Faculty of Pharmaceutical Sciences (UI)
dc.contributor.school Heilbrigðisvísindasvið (HÍ)
dc.contributor.school School of Health Sciences (UI)


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