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Synthesis and evaluation of cyclopentane-based muraymycin analogs targeting MraY
Seung-Hwa Kwak1, Won Young Lim1, Aili Hao2
1Department of Chemistry, Duke University, Durham, NC, 27708, United States.
Abstract:
Antibiotic resistance is one of the most challenging global health issues and presents an urgent need for the development of new antibiotics. In this regard, phospho-MurNAc-pentapeptide translocase (MraY), an essential enzyme in the early stages of peptidoglycan biosynthesis, has emerged as a promising new antibiotic target. We recently reported the crystal structures of MraY in complex with representative members of naturally occurring nucleoside antibiotics, including muraymycin D2. However, these nucleoside antibiotics are synthetically challenging targets, which limits the scope of medicinal chemistry efforts on this class of compounds. To gain access to active muraymycin analogs with reduced structural complexity and improved synthetic tractability, we prepared and evaluated cyclopentane-based muraymycin analogs for targeting MraY. For the installation of the 1,2-syn-amino alcohol group of analogs, the diastereoselective isocyanoacetate aldol reaction was explored. The structure-activity relationship analysis of the synthesized analogs suggested that a lipophilic side chain is essential for MraY inhibition. Importantly, the analog 20 (JH-MR-23) showed antibacterial efficacy against Staphylococcus aureus. These findings provide insights into designing new muraymycin-based MraY inhibitors with improved chemical tractability.
Insights
Researchers developed simpler muraymycin analogs to combat antibiotic resistance. A novel analog demonstrated antibacterial activity against Staphylococcus aureus, offering a promising new avenue for developing effective MraY inhibitors.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Drug Discovery
Background:
- Antibiotic resistance is a critical global health threat, necessitating novel therapeutic agents.
- Phospho-MurNAc-pentapeptide translocase (MraY) is a validated target for new antibiotics due to its essential role in peptidoglycan biosynthesis.
- Existing nucleoside antibiotics targeting MraY, like muraymycin D2, are synthetically complex, hindering medicinal chemistry optimization.
Purpose of the Study:
- To design and synthesize simplified muraymycin analogs with improved synthetic accessibility.
- To evaluate the structure-activity relationships of these analogs for MraY inhibition.
- To identify potent MraY inhibitors with potential antibacterial activity.
Main Methods:
- Synthesis of cyclopentane-based muraymycin analogs.
- Utilized the diastereoselective isocyanoacetate aldol reaction for stereoselective synthesis.
- Performed structure-activity relationship (SAR) studies to identify key inhibitory features.
- Assessed antibacterial efficacy against Staphylococcus aureus.
Main Results:
- Successfully synthesized novel muraymycin analogs with reduced structural complexity.
- Identified a lipophilic side chain as crucial for MraY inhibition.
- Analog 20 (JH-MR-23) exhibited significant antibacterial activity against Staphylococcus aureus.
- Established structure-activity relationships guiding future inhibitor design.
Conclusions:
- Simplified muraymycin analogs targeting MraY can be effectively synthesized.
- A lipophilic side chain is essential for potent MraY inhibition.
- Analog JH-MR-23 demonstrates potential as a lead compound for new antibiotics against Staphylococcus aureus.
- These findings facilitate the development of more tractable MraY inhibitors to address antibiotic resistance.
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