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

[Image: see text] 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 includ...

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Autores principales: Kulkarni, Amogh, Soni, Isha, Kelkar, Dhanashree S., Dharmaraja, Allimuthu T., Sankar, Rathinam K., Beniwal, Gaurav, Rajendran, Abinaya, Tamhankar, Sharvari, Chopra, Sidharth, Kamat, Siddhesh S., Chakrapani, Harinath
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660313/
https://www.ncbi.nlm.nih.gov/pubmed/31241934
http://dx.doi.org/10.1021/acs.jmedchem.9b00774
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author Kulkarni, Amogh
Soni, Isha
Kelkar, Dhanashree S.
Dharmaraja, Allimuthu T.
Sankar, Rathinam K.
Beniwal, Gaurav
Rajendran, Abinaya
Tamhankar, Sharvari
Chopra, Sidharth
Kamat, Siddhesh S.
Chakrapani, Harinath
author_facet Kulkarni, Amogh
Soni, Isha
Kelkar, Dhanashree S.
Dharmaraja, Allimuthu T.
Sankar, Rathinam K.
Beniwal, Gaurav
Rajendran, Abinaya
Tamhankar, Sharvari
Chopra, Sidharth
Kamat, Siddhesh S.
Chakrapani, Harinath
author_sort Kulkarni, Amogh
collection PubMed
description [Image: see text] 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.
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spelling pubmed-66603132019-07-26 Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus Kulkarni, Amogh Soni, Isha Kelkar, Dhanashree S. Dharmaraja, Allimuthu T. Sankar, Rathinam K. Beniwal, Gaurav Rajendran, Abinaya Tamhankar, Sharvari Chopra, Sidharth Kamat, Siddhesh S. Chakrapani, Harinath J Med Chem [Image: see text] 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. American Chemical Society 2019-06-26 2019-07-25 /pmc/articles/PMC6660313/ /pubmed/31241934 http://dx.doi.org/10.1021/acs.jmedchem.9b00774 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Kulkarni, Amogh
Soni, Isha
Kelkar, Dhanashree S.
Dharmaraja, Allimuthu T.
Sankar, Rathinam K.
Beniwal, Gaurav
Rajendran, Abinaya
Tamhankar, Sharvari
Chopra, Sidharth
Kamat, Siddhesh S.
Chakrapani, Harinath
Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus
title Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus
title_full Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus
title_fullStr Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus
title_full_unstemmed Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus
title_short Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus
title_sort chemoproteomics of an indole-based quinone epoxide identifies druggable vulnerabilities in vancomycin-resistant staphylococcus aureus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660313/
https://www.ncbi.nlm.nih.gov/pubmed/31241934
http://dx.doi.org/10.1021/acs.jmedchem.9b00774
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