A Direct-to-Biology Platform for Rapid Covalent Antibiotic Discovery
- 1Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden, Netherlands, 2333 CC
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.
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BibTeX
@misc{voort2026directtobiology,
title = {{A Direct-to-Biology Platform for Rapid Covalent Antibiotic Discovery}},
author = {Storm van der Voort and Tessa Goté and Sophie van ‘t Ooster and Berend Gagestein and Bogdan I. Florea and Richard J. B. H. N. van den Berg and Zachary Armstrong and Herman S. Overkleeft and Stephan M. Hacker},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010946/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010946/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A Direct-to-Biology Platform for Rapid Covalent Antibiotic Discovery
AU - Storm van der Voort
AU - Tessa Goté
AU - Sophie van ‘t Ooster
AU - Berend Gagestein
AU - Bogdan I. Florea
AU - Richard J. B. H. N. van den Berg
AU - Zachary Armstrong
AU - Herman S. Overkleeft
AU - Stephan M. Hacker
PY - 2026
DA - 2026/10/23
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010946/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010946/v1
AB - 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.
ER -