Direct-to-biology screen of crude chloroacetamides yields covalent anti-MRSA hits
- Diazo transfer followed by copper-catalyzed azide-alkyne cycloaddition was used to assemble a library of 720 chloroacetamides in crude form within days, with no purification before testing.
- Phenotypic screening against MRSA gave hits that, on resynthesis, largely retained their activity, supporting the reliability of crude-mixture screening.
- In situ chemoproteomics showed the best hits selectively engage the essential enzyme HMG-CoA synthase; target validation and a co-crystal structure clarified the binding mode.
- The workflow combines library synthesis, hit finding and target identification in a single campaign.
💡 Points
How much of this hit list is simply chloroacetamide warhead reactivity? That is my first worry, since chloroacetamides are the cheap end of covalent chemistry. Hits surviving resynthesis is reassuring, and selective HMG-CoA synthase engagement with a co-crystal is the real prize: it gives a binding-mode hypothesis for tuning the scaffold and a reason to test milder warheads.
A Direct-to-Biology Platform for Rapid Covalent Antibiotic Discovery ↗