9LWW

Crystal structure of dehydrogenase/isomerase FabX from Helicobacter pylori in complex with inhibitor 47

This is a non-PDB format compatible entry.

Summary for 9LWW

• Entry DOI: 10.2210/pdb9lww/pdb
• Descriptor: 2-nitropropane dioxygenase, FLAVIN MONONUCLEOTIDE, IRON/SULFUR CLUSTER, ... (5 entities in total)
• Functional Keywords: fatty acid biosynthesis, dehydrogenase, isomerase, fabx, biosynthetic protein
• Biological source: Helicobacter pylori
• Total number of polymer chains: 1
• Total formula weight: 40905.43

Authors

Zhang, L.,Zhang, L. (deposition date: 2025-02-17, release date: 2025-12-24)

Primary citation

Ruan, X.,Zhang, L.,Dong, L.,Wang, Y.,Zeng, L.,Yang, M.,Bi, H.,Feng, M.,Zhang, L.,Zhou, L.
Discovery of 1,3,4-Thiadiazole Sulfonamide-Based Potent Inhibitors against the Unsaturated Fatty Acid Synthase FabX of Helicobacter pylori.
J.Med.Chem., 68:17175-17188, 2025

PubMed Abstract: Unsaturated fatty acids (UFAs) are essential for the membrane function in most bacteria. In (), a gastric pathogen, UFA biosynthesis depends on the bifunctional dehydrogenase/isomerase FabX, a promising target against . Herein, we report the first FabX inhibitor, (compound , IC = 3.7 ± 0.2 μM), identified via high-throughput screening and featuring a 1,3,4-thiadiazole sulfonamide scaffold. The costructure of FabX- reveals occupancy of the L-shaped substrate-binding tunnel via hydrophobic interactions and hydrogen bonds. Structure-based optimization led to more potent derivatives, among which compound showed potent inhibition (IC = 0.128 ± 0.002 μM), representing a 29-fold improvement. Compound also demonstrated strong antibacterial activity (MIC = 0.5-1 μg/mL), when combined with membrane permeabilizers, efflux pump inhibitors, and clarithromycin, and exhibited narrow-spectrum efficacy against , providing a novel strategy for anti- therapy.

PubMed: 40811148
DOI: 10.1021/acs.jmedchem.5c00654

Experimental method

X-RAY DIFFRACTION (1.7 Å)