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bioRxiv · 10.64898/2026.02.13.705707

Dual Screen for Gut Metabolites Suppressing Enterobacterial Growth and Invasiveness Reveals Structure - Activity Relationships among Anti-Infective Indoles

Bergholtz, A.·Lin, W.·Kaur, A.·Bhetwal, A.·Di Martino, M. L.·Eriksson, J.·Globisch, D.·Sellin, M. E.
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Abstract

The antibiotic resistance crisis makes characterization of new anti-infective molecules a pressing matter. Molecules that suppress bacterial growth and survival, virulence, or the combination of these traits, all warrant further exploration. Naturally occurring microbe-host ecosystems, such as the human gut, provide incompletely tapped resources in this regard. We developed a flexible platform to parallelly assess how gut metabolites affect the growth and epithelial cell invasion capacity of the enteropathogens Salmonella enterica Typhimurium (Salmonella) and Shigella flexneri. By screening a gut metabolite library, the assays identified multiple anti-infective compound classes and extended previously reported antibacterial activities for e.g. medium chain fatty acids, bile acids, purine nucleotides, and indole. Importantly, a targeted follow-up screen combined with chemical biology iterations showed how the anti-infective activity of indole is impacted by its derivatization. Specifically, a methyl group at either of the carbons of the indole scaffold potentiated the suppressive effect on type-III-secretion-system-mediated virulence, flagellar motility (for Salmonella), and growth, in a concentration-dependent manner. By contrast, N1-methylation markedly attenuated the activity of indole and its C-derivatized versions. The study, hence, offers assays for dual growth and virulence analysis of invasive enterobacteria exposed to anti-infective candidate molecules, and informs on structure-activity relationships among indole metabolites.

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Bergholtz, A., Lin, W., Kaur, A., Bhetwal, A., Di Martino, M. L., Eriksson, J., Globisch, D., Sellin, M. E.. 2026-02-13. Dual Screen for Gut Metabolites Suppressing Enterobacterial Growth and Invasiveness Reveals Structure - Activity Relationships among Anti-Infective Indoles. https://doi.org/10.64898/2026.02.13.705707

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