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) |