9S5X

Crystal structure of Neisseria gonorrhoeae FabI in complex with NADH and (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide

This is a non-PDB format compatible entry.

Summary for 9S5X

• Entry DOI: 10.2210/pdb9s5x/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], (~{E})-~{N}-methyl-~{N}-[(3-methyl-1-benzofuran-2-yl)methyl]-3-[(2~{R},3~{S})-2-methyl-3-oxidanyl-4-oxidanylidene-1,2,3,5-tetrahydropyrido[2,3-b][1,4]diazepin-8-yl]prop-2-enamide, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: enoyl-[acyl-carrier-protein] reductase [nadh] neisseria gonorrhoeae, hydrolase, oxidoreductase
• Biological source: Neisseria gonorrhoeae
• Total number of polymer chains: 2
• Total formula weight: 62292.03

Authors

Ronin, C.,Gerusz, V.,Ciesielski, F. (deposition date: 2025-07-30, release date: 2025-08-20, Last modification date: 2025-10-01)

Primary citation

Gerusz, V.,Regenass, P.,Rousseau, Q.,Moraine, V.,Dao, J.,Lave, X.,Das, S.,Hue Perron, J.,Fajas Descamps, L.,Bravo, J.,Dieppois, G.,Kaplan, N.,Lefebre, M.,Altomari, D.,Romanov, V.,Finn, T.,Daram, P.,Bernardini, F.,Gross, M.,Lysek, R.,Adam, A.,Pohin, D.,Maio, M.,Tatsis, V.,Sunose, M.,Ronin, C.,Ciesielski, F.,Ahlstrand, J.,Jacobsson, S.,Unemo, M.,Cameron, D.R.
The bactericidal FabI inhibitor Debio 1453 clears antibiotic-resistant Neisseria gonorrhoeae infection in vivo.
Nat Commun, 16:8309-8309, 2025

PubMed 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.

PubMed: 40968127
DOI: 10.1038/s41467-025-63508-w

Experimental method

X-RAY DIFFRACTION (1.34 Å)