Fellow's research: A new therapeutic target for treating drug-resistant bacterial infection
14 Aug 2019
Dr Siddhesh S. Kamat, Intermediate Fellow
Indian Institute of Science Education and Research, Pune
Our recently published study underscores the need to discover novel drug targets to tackle infections caused by pathogenic antibiotic-resistant Staphylococcus aureus (S. aureus), a gram-positive bacterium. Using tailored small molecules that specifically target the cysteine residues driving reactions in proteins involved in transcription, we have developed a new strategy to kill antibiotic-resistant strains of S. aureus, including the vancomycin-resistant S. aureus (VRSA).
The graphical abstract
Anti-microbial resistance (AMR), the ability of microorganisms to withstand antimicrobials, is a global health challenge today and remedies that could help in reducing and/or tackling this problem are in urgent need. The clinical pathogen S. aureus and its forms resistant to antibiotics (e.g. VRSA) cause severe skin and throat infections and infect immune-compromised patients in hospitals. With the existing pool of antibiotics, soon becoming ineffective, improved and/or new antibacterial agents with novel biological targets, which are molecules on the microbes that the antimicrobials act on, are in great demand to combat drug-resistant bugs. With this idea in mind, we set forth to design a series of bioactive compounds that would inhibit key S. aureus proteins, and thus prevent bacterial proliferation.
The amino acid cysteine is poorly abundant yet catalytically important for most proteins modulating different cellular processes (e.g. redox biology, proteolysis), given the reactive nature of its thiol functional group. Pharmacologically, this unique reactivity of cysteine with crucial physiological consequences has been leveraged to make covalent inhibitors, a class of therapeutic agents that bind covalently to their target proteins and are used clinically to treat different human cancers. Thus, using this background and the available literature precedence, we hypothesized that we could synthetically tailor reactive epoxides (a chemical scaffold known to react with cysteines) to irreversibly modify conserved cysteines of physiologically important proteins in VRSA, and in doing so, perturb cellular homeostasis and ultimately kill this disease-causing bacteria.
In this study, we describe the chemical synthesis of indole-based quinone epoxides, a new class of anti-bacterial compounds showing potent inhibitory activity against several clinically-derived, antibiotic-resistant S. aureus, including VRSA. Next, using a functional proteomics strategy termed chemoproteomics or activity-based protein profiling, we identify and biochemically validate key transcriptional factors (also known as virulence factors that enable the pathogen to replicate and disseminate in the host) in S. aureus, as biological targets for this compound class. Thus, in this study, we report for the first time, novel protein targets in VRSA that were previously thought to be “undruggable”. The chemical tools used and biological targets described in this study present a new therapeutic approach to manage VRSA and other antibiotic-resistant bacterial infections.
Chemoproteomics of an indole-based quinone-epoxide identifies druggable vulnerabilities in vancomycin resistant Staphylococcus aureus. Amogh Kulkarni, Isha Soni, Dhanashree Kelkar, Allimuthu T Dharmaraja, Rathinam Sankar, Gaurav Beniwal, Abinaya Rajendran, Sharvari Tamhankar, Sidharth Chopra*, Siddhesh S. Kamat*, Harinath Chakrapani*. Journal of Medicinal Chemistry. July 2019.