Discovery of 1,3,4-Thiadiazole Sulfonamide-Based Potent Inhibitors against the Unsaturated Fatty Acid Synthase FabX of Helicobacter pylori

Unsaturated fatty acids (UFAs) are essential for the
membrane function
in most bacteria. In Helicobacter pylori (H. pylori), a gastric pathogen,
UFA biosynthesis depends on the bifunctional dehydrogenase/isomerase
FabX, a promising target against H. pylori. Herein, we report the first FabX inhibitor, P61G11 (compound 1, IC50 = 3.7 ± 0.2 μM),
identified via high-throughput screening and featuring a 1,3,4-thiadiazole
sulfonamide scaffold. The costructure of FabX–1 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 47 showed
potent inhibition (IC50 = 0.128 ± 0.002 μM),
representing a 29-fold improvement. Compound 47 also
demonstrated strong in vitro antibacterial activity
(MIC = 0.5–1 μg/mL), when combined with membrane permeabilizers,
efflux pump inhibitors, and clarithromycin, and exhibited narrow-spectrum
efficacy against H. pylori, providing
a novel strategy for anti-H. pylori therapy.