With the improvement of analytical technologies, the Chemical Biology field now recognizes that the overwhelming majority of small molecule metabolites that are found in any organism remain unknown. It is believed that some of the uncharacterized metabolites from this so-called and reproducible ‘dark matter’ of the metabolome could regulate complex molecular interactions that significantly influence human health and disease. To explore this question more broadly, we highlight four novel metabolic pathways that we have characterized in the well-studied gut bacterium, E. coli. These include: 1) folate/monapterin pathway-derived pteridines that upregulate IL-10 in the host and reduce disease symptoms in a colitis mouse model; 2) indole-functionalized metabolites that regulate IL-6 in the host and are structurally conserved with products of the plant innate immune system; 3) pyrazinones that regulate bacterial virulence programs and IL-8 in the host; and 4) polyketide synthase-nonribosomal peptide synthetase hybrid products that crosslink DNA and are associated with colorectal cancer initiation. Based on these findings and other novel metabolic pathways that we are currently characterizing in E. coli, we argue that much remains to be discovered even in organisms that have been studied for generations.

E. coli metabolism at the host-bacteria interface

ACS Fall 2021

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