Direct-to-biology platform speeds covalent antibiotic discovery against MRSA
- A diazo transfer and copper-catalyzed click sequence built a large combinatorial set of crude chloroacetamides within days, screened against MRSA without purification.
- Resynthesized hits largely retained their activity, supporting the reliability of screening crude mixtures.
- In situ chemoproteomics pointed to selective engagement of HMG-CoA synthase, validated as the target and rationalized by a co-crystal structure.
- Library synthesis, hit finding and target identification run in one campaign.
💡 Points Based on the abstract
Chloroacetamides are blunt warheads, so my first question is proteome-wide selectivity, and the in situ chemoproteomics answering with HMG-CoA synthase is reassuring. Targeting the mevalonate pathway in Gram-positives is a refreshing departure from beta-lactam and ribosome chemotypes. The caveat: a crystal structure of a covalent adduct says little about whether non-covalent recognition can be tuned toward a tamer warhead.
A Direct-to-Biology Platform for Rapid Covalent Antibiotic Discovery ↗