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

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 infe...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2019-07, Vol.62 (14), p.6785-6795
Main Authors: 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
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - pharmacology
Benzoquinones - chemistry
Benzoquinones - pharmacology
Drug Discovery
Epoxy Compounds - chemistry
Epoxy Compounds - pharmacology
Humans
Indoles - chemistry
Indoles - pharmacology
Models, Molecular
Proteomics
Staphylococcal Infections - drug therapy
Staphylococcus aureus - drug effects
Vancomycin - pharmacology
Vancomycin Resistance - drug effects
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b00774