2. Academic Validation
  3. The bactericidal FabI inhibitor Debio 1453 clears antibiotic-resistant Neisseria gonorrhoeae infection in vivo

The bactericidal FabI inhibitor Debio 1453 clears antibiotic-resistant Neisseria gonorrhoeae infection in vivo

  • Nat Commun. 2025 Sep 18;16(1):8309. doi: 10.1038/s41467-025-63508-w.
Vincent Gerusz 1,  Pierre Regenass 2,  Quentin Rousseau 2,  Victor Moraine 2,  Justine Dao 3,  Xavier Lavé 3,  Shampa Das 4,  Josée Hue Perron 3,  Laurence Fajas Descamps 3,  Juan Bravo 3,  Guennaëlle Dieppois 3,  Nachum Kaplan 5,  Matthew Lefebre 5,  Deanna Altomari 5,  Vladimir Romanov 5,  Terry Finn 3,  Pierre Daram 3,  Francesca Bernardini 3,  Michaël Gross 2,  Robert Lysek 2,  Aurélien Adam 2,  Danig Pohin 2,  Maurizio Maio 2,  Vasileios Tatsis 6,  Mihiro Sunose 6,  Céline Ronin 7,  Fabrice Ciesielski 7,  Josefine Ahlstrand 8,  Susanne Jacobsson 8,  Magnus Unemo 8 9,  David R Cameron 10
Affiliations

Affiliations

  • 1 Debiopharm Research and Manufacturing SA, Martigny, Switzerland. vincent.gerusz@debiopharm.com.
  • 2 Debiopharm Research and Manufacturing SA, Martigny, Switzerland.
  • 3 Debiopharm International SA, Lausanne, Switzerland.
  • 4 Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology, University of Liverpool, Liverpool Health Partners, Liverpool, UK.
  • 5 Nobelex Biotech, Inc., Toronto, ON, Canada.
  • 6 Sygnature Discovery, Biocity, Nottingham, UK.
  • 7 Novalix, Strasbourg, France.
  • 8 WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
  • 9 Institute for Global Health, University College London (UCL), London, UK.
  • 10 Debiopharm International SA, Lausanne, Switzerland. david.cameron@debiopharm.com.
PMID: 40968127 DOI: 10.1038/s41467-025-63508-w
Abstract

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.

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