The bactericidal FabI inhibitor Debio 1453 clears antibiotic-resistant Neisseria gonorrhoeae infection in vivo
Gonorrhoea is a prevalent sexually transmitted infection caused by the bacterial pathogen Neisseria gonorrhoeae. N. gonorrhoeae has demonstrated a remarkable capacity to evolve antibiotic resistance, with emerging strains that show resistance to all standard treatment options. The development of new antibiotics for gonorrhoea, especially those with novel targets and no pre-existing resistance, is critical. One such untapped antibacterial target in N. gonorrhoeae is FabI, an enoyl-acyl carrier protein reductase enzyme that is essential for fatty acid biosynthesis in this pathogen. In the current report, structure-based drug design using novel N. gonorrhoeae FabI inhibitor co-crystals guides medicinal chemistry toward increasing potency in the sub-nanomolar range and drives the discovery of Debio 1453. Debio 1453 is optimized for activity against N. gonorrhoeae and is highly active in vitro against diverse N. gonorrhoeae isolates including those resistant to the last remaining treatment options. Additionally, the compound presents a low propensity for selection of mutants with reduced susceptibility. Debio 1453 is efficacious in vivo against N. gonorrhoeae isolates with clinically relevant multi-drug resistance phenotypes in a murine vaginal gonorrhoea infection model underscoring Debio 1453 as a promising candidate for the treatment of gonorrhoea.
Authors
- David R. Cameron (ORCID: https://orcid.org/0000-0003-3700-5625)
- Fabrice Ciesielski (ORCID: https://orcid.org/0000-0002-4077-7741)
- Robert Łysek
- Jennifer Dao
- Josefine Ahlstrand
- Matthew Lefebre
- Pierre Regenass
- Francesca Bernardini
- Terry Finn
- Maurizio Maio
- Ana-Maria Adam (ORCID: https://orcid.org/0009-0004-8695-5381)
- Nachum Kaplan
- Deanna Altomari
- Vasileios Tatsis (ORCID: https://orcid.org/0000-0001-8610-3139)
- V. Romanov
- Magnus Unemo (ORCID: https://orcid.org/0000-0003-1710-2081)
- Shampa Das (ORCID: https://orcid.org/0000-0002-2540-4816)
- Guennaëlle Dieppois (ORCID: https://orcid.org/0000-0002-8319-4079)
- Céline Ronin (ORCID: https://orcid.org/0000-0002-0930-5316)
- Vincent Gerusz (ORCID: https://orcid.org/0009-0005-4583-8733)
- Mihiro Sunose
- Pierre Daram
- Susanne Jacobsson
- Laurence Descamps
- Juan Bravo
- Matthew Gross
- Danig Pohin
- Quentin Rousseau
- Victor Moraine
- Xavier Lavé
- Josée Hue Perron
Institutions
- University of Liverpool (GB)
- Örebro University (SE)
- Debiopharm (Switzerland) (CH)
- NOVASiC (France) (FR)
- Vancouver Biotech (Canada) (CA)
- Signature Research (United States) (US)
- University College London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-18
- DOI
- https://doi.org/10.1038/s41467-025-63508-w
- Citations
- 1
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 0.59
Funders
- U.S. Department of Health and Human Services
- Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator
- Department of Health and Social Care
- Bundesministerium für Bildung und Forschung
- Biomedical Advanced Research and Development Authority
- National Institute of Allergy and Infectious Diseases