Metabodefense

Products of the body’s own metabolism not only have a regulatory effect on the immune system, but can also influence the growth or persistence of bacteria. The contribution of host metabolites in antimicrobial defence is still largely unexplored. We postulated that a targeted modulation of the host metabolism can inhibit pathogen growth and develop an antimicrobial efficacy against persisters. We investigated this paradigmatically with a Salmonella infection model. We used methods of bioinformatics and machine learning to identify new antimicrobially effective target structures anchored in the metabolism from highly complex metabolome and transcriptome data. In the Jantsch-Lab macrophages were infected with Salmonella and different signalling pathways of the macrophages will be disturbed. In the Dettmer-Lab, genome-wide gene expression analyses (in collaboration with the Genomics Core Unit of the University of Regensburg), comprehensive metabolome analyses as well as targeted quantitative metabolite and metabolic tracer analyses are performed on samples obtained from infected macrophages. The Spang group develops predictive models of pathogen control, network modelling of host-pathogen interaction and causal models for the identification of putative antimicrobial target structures. The new candidates are then validated in vitro and in vivo in the Jantsch-Lab and Dettmer-Lab. This provides the basis for new approaches to host-based therapy of multi-resistant pathogens.

Within the Metabodefense project, the network partners succeeded in systematically decoding the host cell metabolism as a central control element of antimicrobial defense and in making it therapeutically accessible. Based on more than 40 targeted metabolic interventions in macrophages, the team comprehensively analyzed how manipulating individual metabolic pathways affects the control of intracellular pathogens. Two metabolic axes emerged as particularly decisive: choline metabolism, whose modulation strongly influenced the intracellular replication of Salmonella, and a neurotransmitter-associated metabolic pathway, where pharmacological inhibition significantly enhanced immune defense in vitro and in animal models. In parallel, the researchers identified the MI4 signature, a four-metabolite profile capable of reliably distinguishing infected from non-infected cells—across multiple gram-negative and gram-positive pathogens. Another key discovery was the pivotal role of the HIF-1α signaling pathway, which not only shapes the immune response but also regulates the synthesis of antimicrobial metabolites, establishing a conceptual link between hypoxia, cellular metabolism, and pathogen control. Together, these findings revealed novel therapeutic targets that could complement or even alleviate the pressure on classical antibiotic therapies.