{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden, Netherlands, 2333 CC"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Storm van der Voort",
      "orcid": "0000-0001-8177-1496"
    },
    {
      "affs": [
        0
      ],
      "name": "Tessa Goté"
    },
    {
      "affs": [
        0
      ],
      "name": "Sophie van ‘t Ooster"
    },
    {
      "affs": [
        0
      ],
      "name": "Berend Gagestein"
    },
    {
      "affs": [
        0
      ],
      "name": "Bogdan I. Florea"
    },
    {
      "affs": [
        0
      ],
      "name": "Richard J. B. H. N. van den Berg"
    },
    {
      "affs": [
        0
      ],
      "name": "Zachary Armstrong"
    },
    {
      "affs": [
        0
      ],
      "name": "Herman S. Overkleeft"
    },
    {
      "affs": [
        0
      ],
      "name": "Stephan M. Hacker",
      "orcid": "0000-0001-5420-4824"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0gg2m3v81kd1b.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010946/v1",
  "fulltext_url": null,
  "id": "0gg2m3v81kd1b",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010946/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1605|Click Chemistry and Applications"
    ]
  ],
  "openalex": "W7223344233",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010946/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/0gg2m3v81kd1b.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:26Z",
      "native_id": "10.26434/chemrxiv.15010946",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010946/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Click Chemistry and Applications",
      "subfield": "organic"
    }
  ],
  "title": "A Direct-to-Biology Platform for Rapid Covalent Antibiotic Discovery",
  "title_text": "A Direct-to-Biology Platform for Rapid Covalent Antibiotic Discovery",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:26Z",
  "url": "https://research.draconitic.com/paper/0gg2m3v81kd1b",
  "venue": "ChemRxiv",
  "versions": []
}