Premethylenomycin C lactone
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| Formula | C9H10O3 |
| Molar mass | 166.176 g·mol−1 |
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Premethylenomycin C lactone is a natural product with potent antibiotic activity, effective against drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).[1][2]
Discovery
[edit]The compound was identified unintentionally during investigations of the methylenomycin biosynthetic gene cluster in Streptomyces coelicolor, a bacterium found in soil.[1] Genetic blockade of a specific enzymatic step by deletion of the mmyE gene led to the accumulation and isolation of previously uncharacterized intermediates, including pre-methylenomycin C and its lactone derivative.[2][3]
In the biosynthetic pathway that produces methylenomycin A, premethylenomycin C lactone is an early intermediate. Hydrolysis of the lactone ring followed by dehydration yields methylenomycin C, which is subsequently oxidized to form the epoxide methylenomycin A.[2]
Metabolism of premethylenomycin C lactone
Bioactivity
[edit]Compared with methylenomycin A and methylenomycin C, premethylenomycin C and its lactone precursor exhibit antimicrobial activity that is one to two orders of magnitude greater against a range of Gram-positive bacteria, including antibiotic-resistant isolates of Staphylococcus aureus and Enterococcus faecium.[2] It also does not have the α-methylene-γ-butyrolactone pharmacophore of methylenomycin A and methylenomycin C, meaning it has a different mode of action.[2] These properties highlight the compounds in this metabolic series as potential leads for developing new antibiotics to combat antimicrobial resistance.[2]
Chemistry
[edit]Beyond its natural production, premethylenomycin C lactone can be prepared synthetically via a diastereoselective phosphine-mediated (3 + 2) cycloaddition reaction, providing a route for larger‑scale preparation and structure–activity relationship studies.[4]
References
[edit]- ^ a b Naddaf M (October 2025). "Powerful new antibiotic that can kill superbugs discovered in soil bacteria". Nature. doi:10.1038/d41586-025-03595-3. PMID 41174166.
- ^ a b c d e f Corre C, Idowu GA, Song L, Whitehead ME, Alkhalaf LM, Challis GL (November 2025). "Discovery of Late Intermediates in Methylenomycin Biosynthesis Active against Drug-Resistant Gram-Positive Bacterial Pathogens". Journal of the American Chemical Society. 147 (44): 40554–40561. Bibcode:2025JAChS.14740554C. doi:10.1021/jacs.5c12501. PMC 12593393. PMID 41145303.
- ^ Adams B (28 October 2025). "Warwick University scientists help find 'hidden' antibiotic". www.bbc.com.
- ^ Wright AI, Zhang C, Cao J, Nakano Y, Sánchez-Jiménez L, DeBono J, et al. (August 2025). "Phosphine-Mediated (3 + 2) Cycloaddition of Electron-Poor Terminal Alkynes: A Concise Route to Premethylenomycin C Lactone". The Journal of Organic Chemistry. 90 (31): 11230–11236. doi:10.1021/acs.joc.5c01179. PMID 40728462.
Further reading
[edit]- Boschelli D, Scarborough Jr RM, Smith III AB (January 1981). "Total synthesis of (±)-desepoxy-4, 5-didehybromethylenomycin A". Tetrahedron Letters. 22 (1): 19–22. doi:10.1016/0040-4039(81)80029-9.
- Takahashi Y, Kosugi H, Uda H (1982). "Synthesis of (±)-desepoxy-4, 5-didehydromethylenomycin A". Chemistry Letters. 11 (6): 815–816. doi:10.1246/cl.1982.815.
- Au-Yeung BW, Wang Y (1985). "Allylsilane in synthesis: new syntheses of (±)-desepoxy-4, 5-didehydromethylenomycin A and (±)-xanthocidin". Journal of the Chemical Society, Chemical Communications (12): 825–827. doi:10.1039/C39850000825.