Year: 2026
Type: preprint
Abstract: The rise of antibiotic-resistant bacterial infections has created a critical need for new antibiotics. While natural product-based covalent antibiotic classes such as the β-lactams are highly effective, exploration of synthetic covalent antibiotics remains limited. Here, we present a direct-to-biology platform for covalent antibiotic discovery. Using tandem diazo transfer and copper-catalyzed azide-alkyne cycloaddition, we combinatorially synthesized 720 crude chloroacetamides within a matter of days and screened these for activity against methicillin-resistant Staphylococcus aureus (MRSA). By resynthesis and retesting, almost all hits were confirmed to be active, having potency profiles comparable to those of the initial screen. In situ chemoproteomic analyses revealed selective engagement of the essential enzyme HMG-CoA synthase by the most promising hits. We validated this target and obtained a co-crystal structure to better understand the binding mode of the compound. Altogether, this platform generates large libraries of covalently reactive compounds, identifies active compounds, and finds their molecular targets within a single screening campaign.
Source: ChemRxiv
Institution: Leiden University
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7223344233