Antagonist Targeting the Species‐Specific Fatty Acid Dehydrogenase/Isomerase FabX for Anti‐<i>H. pylori</i> Infection

Helicobacter pylori (H. pylori) is a group-1 definite pathogenic carcinogen that infects approximately half of the global population, yet no species-specific chemotherapy has yet been developed. It is previously discovered that H. pylori encodes an atypical dehydrogenase/isomerase FabX in the Type-II fatty acid biosynthesis pathway to produce unsaturated fatty acids (UFA) as well as superoxide (ROS). Here, it is demonstrated that FabX is essential for H. pylori growth and gastric colonization by retaining UFA synthesis and producing ROS, respectively, and is a species-specific anti-H. pylori drug target. The first small molecule inhibitor FBX-1991 against FabX, which inhibits the enzymatic activity with an IC₅₀ value of 0.158 × 10^-6 m in vitro, is developed. FBX-1991 binds inside the catalytic tunnel of FabX, disrupts the conformation of the key catalytic loop, and prevents the insertion of the acyl substrate for catalysis. Further in vivo studies suggest that FBX-1991 inhibits the H. pylori growth by partially inhibiting UFA synthesis and ROS excretion through targeting FabX. This study identifies a species-specific anti-H. pylori drug target, FabX, and discovers the first highly potent and selective FabX inhibitor against H. pylori infection, which provides the molecular basis for developing species-specific anti-H. pylori chemotherapy.