F3385-1872

F3385-1872 is a selective small molecule inhibitor of the bacterial enzyme histidine ammonia-lyase (HutH), specifically targeting the pathobiont *Fusobacterium nucleatum* (Fn). Identified through structure-based virtual screening of over 70,000 compounds, F3385-1872 prevents the degradation of luminal histidine by Fn. This metabolic blockade addresses a key driver of intestinal inflammation, as histidine depletion normally triggers MAPK activation in dendritic cells, leading to an immunogenic phenotype (CD80+CD86+) and a Th17/Treg imbalance. In preclinical models of DSS- and Fn-exacerbated colitis, the compound significantly reduced the production of pro-inflammatory cytokines such as IL-6, IL-1β, and IL-23, and restored immune homeostasis. Notably, F3385-1872 achieves these effects without disrupting the overall gut microbiota composition or showing systemic toxicity, positioning it as a potential microbiome-targeted therapy for inflammatory bowel disease (IBD).