Sesamol hinders the proliferation of intracellular bacteria by promoting fatty acid metabolism and decreasing excessive inflammation

The extraintestinal pathogenic Escherichia coli (ExPEC) is a significant zoonotic bacterial pathogen that can cause severe infections and potentially cross-transmit between different hosts. The treatment of clinical bacterial infections is challenging because of the increasingly severe problem of drug resistance. The development of new strategies for managing bacterial infections is essential. Host-acting antibacterial compound (HAC)-based host-directed therapy (HDT) has emerged as a promising approach to combat bacterial infections by targeting host-pathogen interactions and bacterial intracellular survival strategies. In this study, we conducted a cell-based screening to identify compounds that can inhibit the survival and proliferation of ExPEC within host cells. Our screening revealed that sesamol effectively inhibited ExPEC proliferation but had no effect on the natural growth of bacteria. Analysis of the transcriptome data revealed that sesamol has the ability to increase the metabolism of host fatty acids while also suppressing excessive inflammation. Mechanistic studies have shown that sesamol-induced PPAR-β activation is crucial for increased fatty acid metabolism and clearance of intracellular bacteria. Furthermore, sesamol treatment demonstrated protective effects against ExPEC infection in both Galleria mellonella and mouse models, suggesting its potential use for treating diseases caused by intracellular bacterial pathogens and as a lead compound for further development of anti-infection drugs on the basis of the HDT strategy.