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

Vincent Gerusz (), Pierre Regenass, Quentin Rousseau, Victor Moraine, Justine Dao, Xavier Lavé, Shampa Das, Josée Hue Perron, Laurence Fajas Descamps, Juan Bravo, Guennaëlle Dieppois, Nachum Kaplan, Matthew Lefebre, Deanna Altomari, Vladimir Romanov, Terry Finn, Pierre Daram, Francesca Bernardini, Michaël Gross, Robert Lysek, Aurélien Adam, Danig Pohin, Maurizio Maio, Vasileios Tatsis, Mihiro Sunose, Céline Ronin, Fabrice Ciesielski, Josefine Ahlstrand, Susanne Jacobsson, Magnus Unemo and David R. Cameron ()
Additional contact information
Vincent Gerusz: Debiopharm Research and Manufacturing SA
Pierre Regenass: Debiopharm Research and Manufacturing SA
Quentin Rousseau: Debiopharm Research and Manufacturing SA
Victor Moraine: Debiopharm Research and Manufacturing SA
Justine Dao: Debiopharm International SA
Xavier Lavé: Debiopharm International SA
Shampa Das: Liverpool Health Partners
Josée Hue Perron: Debiopharm International SA
Laurence Fajas Descamps: Debiopharm International SA
Juan Bravo: Debiopharm International SA
Guennaëlle Dieppois: Debiopharm International SA
Nachum Kaplan: Inc.
Matthew Lefebre: Inc.
Deanna Altomari: Inc.
Vladimir Romanov: Inc.
Terry Finn: Debiopharm International SA
Pierre Daram: Debiopharm International SA
Francesca Bernardini: Debiopharm International SA
Michaël Gross: Debiopharm Research and Manufacturing SA
Robert Lysek: Debiopharm Research and Manufacturing SA
Aurélien Adam: Debiopharm Research and Manufacturing SA
Danig Pohin: Debiopharm Research and Manufacturing SA
Maurizio Maio: Debiopharm Research and Manufacturing SA
Vasileios Tatsis: Sygnature Discovery
Mihiro Sunose: Sygnature Discovery
Céline Ronin: Novalix
Fabrice Ciesielski: Novalix
Josefine Ahlstrand: Örebro University
Susanne Jacobsson: Örebro University
Magnus Unemo: Örebro University
David R. Cameron: Debiopharm International SA

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63508-w

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