Heterologous Expression of a Cryptic BGC from Bilophila sp. Provides Access to a Novel Family of Antibacterial Thiazoles

Research output: Contribution to journal › Research article › Contributed › peer-review

Contributors

  • Maximilian Hohmann - , Chair of Technical Biochemistry (Author)
  • Denis Iliasov - , Chair of General Microbiology (Author)
  • Martin Larralde - , Leiden University Medical Centre (LUMC) (Author)
  • Widya Johannes - , Klinikum Rechts der Isar (MRI TUM) (Author)
  • Klaus-Peter Janßen - , Klinikum Rechts der Isar (MRI TUM) (Author)
  • Georg Zeller - , Leiden University Medical Centre (LUMC) (Author)
  • Thorsten Mascher - , Chair of General Microbiology (Author)
  • Tobias A M Gulder - , Chair of Technical Biochemistry, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University (Author)

Abstract

Human health is greatly influenced by the gut microbiota and microbiota imbalance can lead to the development of diseases. It is widely acknowledged that the interaction of bacteria within competitive ecosystems is influenced by their specialized metabolites, which act, e.g., as antibacterials or siderophores. However, our understanding of the occurrence and impact of such natural products in the human gut microbiome remains very limited. As arylthiazole siderophores are an emerging family of growth-promoting molecules in pathogenic bacteria, we analyzed a metagenomic data set from the human microbiome and thereby identified the bil-BGC, which originates from an uncultured Bilophila strain. Through gene synthesis and BGC assembly, heterologous expression and mutasynthetic experiments, we discovered the arylthiazole natural products bilothiazoles A-F. While established activities of related molecules indicate their involvement in metal-binding and -uptake, which could promote the growth of pathogenic strains, we also found antibiotic activity for some bilothiazoles. This is supported by biosensor-experiments, where bilothiazoles C and E show P recA -suppressing activity, while bilothiazole F induces P blaZ , a biosensor characteristic for β-lactam antibiotics. These findings serve as a starting point for investigating the role of bilothiazoles in the pathogenicity of Bilophila species in the gut.

Details

Original languageEnglish
Pages (from-to)967-978
Number of pages12
JournalACS synthetic biology
Volume14
Issue number3
Publication statusPublished - 21 Mar 2025
Peer-reviewedYes

External IDs

PubMedCentral PMC11934131
Scopus 85218866595

Keywords

Sustainable Development Goals

Keywords

  • Anti-Bacterial Agents/pharmacology, Bacteroidetes/genetics, Gastrointestinal Microbiome, Humans, Thiazoles/pharmacology