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Anti-Tuberculosis Mur Inhibitors: Structural Insights and the Way Ahead for Development of Novel Agents
Kunal Mehta1, Mihir Khambete1, Arundhati Abhyankar1
1SVKM's Dr Bhanuben Nanavati College of Pharmacy, Mumbai 400056, India.
Abstract:
Mur enzymes serve as critical molecular devices for the synthesis of UDP-MurNAc-pentapeptide, the main building block of bacterial peptidoglycan polymer. These enzymes have been extensively studied for bacterial pathogens such as Escherichia coli and Staphylococcus aureus. Various selective and mixed Mur inhibitors have been designed and synthesized in the past few years. However, this class of enzymes remains relatively unexplored for Mycobacterium tuberculosis (Mtb), and thus offers a promising approach for drug design to overcome the challenges of battling this global pandemic. This review aims to explore the potential of Mur enzymes of Mtb by systematically scrutinizing the structural aspects of various reported bacterial inhibitors and implications concerning their activity. Diverse chemical scaffolds such as thiazolidinones, pyrazole, thiazole, etc., as well as natural compounds and repurposed compounds, have been reviewed to understand their in silico interactions with the receptor or their enzyme inhibition potential. The structural diversity and wide array of substituents indicate the scope of the research into developing varied analogs and providing valuable information for the purpose of modifying reported inhibitors of other multidrug-resistant microorganisms. Therefore, this provides an opportunity to expand the arsenal against Mtb and overcome multidrug-resistant tuberculosis.
Insights
Mur enzymes are crucial for bacterial cell wall synthesis and largely unexplored in Mycobacterium tuberculosis (Mtb). This review explores Mtb Mur enzyme inhibitors for new tuberculosis drug development.
Area of Science:
- Biochemistry and Molecular Biology
- Microbiology
- Drug Discovery
Background:
- Mur enzymes synthesize UDP-MurNAc-pentapeptide, a key component of bacterial peptidoglycan.
- While extensively studied in E. coli and S. aureus, Mur enzymes in Mycobacterium tuberculosis (Mtb) remain underexplored.
- Targeting Mtb Mur enzymes presents a promising strategy against multidrug-resistant tuberculosis.
Purpose of the Study:
- To review the potential of Mtb Mur enzymes as drug targets.
- To analyze structural aspects of known bacterial Mur inhibitors and their implications for Mtb.
- To identify opportunities for developing novel anti-tubercular agents.
Main Methods:
- Systematic review of structural aspects of reported bacterial Mur inhibitors.
- Analysis of diverse chemical scaffolds (thiazolidinones, pyrazole, thiazole) and natural/repurposed compounds.
- In silico evaluation of inhibitor interactions and enzyme inhibition potential.
Main Results:
- Diverse chemical scaffolds show potential for inhibiting Mur enzymes.
- Structural analysis reveals scope for analog development and modification of existing inhibitors.
- In silico studies provide insights into receptor interactions and inhibition mechanisms.
Conclusions:
- Mtb Mur enzymes represent a promising, yet underexplored, target for tuberculosis drug discovery.
- Existing knowledge of inhibitors for other bacteria can be leveraged to design Mtb-specific agents.
- Further research into Mtb Mur enzyme inhibitors can expand therapeutic options against multidrug-resistant tuberculosis.
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