Microbial communities form rich extracellular metabolomes that foster metabolic interactions and promote drug tolerance

Jason S.L. Yu, Clara Correia-Melo, Francisco Zorrilla, Lucia Herrera-Dominguez, Mary Y. Wu, Johannes Hartl, Kate Campbell, Sonja Blasche, Marco Kreidl, Anna Sophia Egger, Christoph B. Messner, Vadim Demichev, Anja Freiwald, Michael Mülleder, Michael Howell, Judith Berman, Kiran R. Patil, Mohammad Tauqeer Alam, Markus Ralser

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)


Microbial communities are composed of cells of varying metabolic capacity, and regularly include auxotrophs that lack essential metabolic pathways. Through analysis of auxotrophs for amino acid biosynthesis pathways in microbiome data derived from >12,000 natural microbial communities obtained as part of the Earth Microbiome Project (EMP), and study of auxotrophic–prototrophic interactions in self-establishing metabolically cooperating yeast communities (SeMeCos), we reveal a metabolically imprinted mechanism that links the presence of auxotrophs to an increase in metabolic interactions and gains in antimicrobial drug tolerance. As a consequence of the metabolic adaptations necessary to uptake specific metabolites, auxotrophs obtain altered metabolic flux distributions, export more metabolites and, in this way, enrich community environments in metabolites. Moreover, increased efflux activities reduce intracellular drug concentrations, allowing cells to grow in the presence of drug levels above minimal inhibitory concentrations. For example, we show that the antifungal action of azoles is greatly diminished in yeast cells that uptake metabolites from a metabolically enriched environment. Our results hence provide a mechanism that explains why cells are more robust to drug exposure when they interact metabolically.

Original languageEnglish
Pages (from-to)542-555
Number of pages14
JournalNature Microbiology
Issue number4
Publication statusPublished - Apr 2022

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology


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