A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis

Nat Commun. 2019 Aug 9;10(1):3611. doi: 10.1038/s41467-019-11538-6.


The formicamycin biosynthetic gene cluster encodes two groups of type 2 polyketide antibiotics: the formicamycins and their biosynthetic precursors the fasamycins, both of which have activity against methicillin-resistant Staphylococcus aureus. Here, we report the formicapyridines which are encoded by the same gene cluster and are structurally and biosynthetically related to the fasamycins and formicamycins but comprise a rare pyridine moiety. These compounds are trace-level metabolites formed by derailment of the major biosynthetic pathway. Inspired by evolutionary logic we show that rational mutation of a single gene in the biosynthetic gene cluster encoding an antibiotic biosynthesis monooxygenase (ABM) superfamily protein leads to a significant increase both in total formicapyridine production and their enrichment relative to the fasamycins/formicamycins. Our observations broaden the polyketide biosynthetic landscape and identify a non-catalytic role for ABM superfamily proteins in type II polyketide synthase assemblages for maintaining biosynthetic pathway fidelity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / biosynthesis*
  • Anti-Bacterial Agents / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Biosynthetic Pathways
  • Metabolic Engineering
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Mixed Function Oxygenases / chemistry*
  • Mixed Function Oxygenases / genetics
  • Multigene Family
  • Mutation
  • Polyketides / metabolism*
  • Protein Domains / physiology*
  • Secondary Metabolism
  • Streptomyces / genetics
  • Streptomyces / metabolism


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Polyketides
  • Mixed Function Oxygenases

Supplementary concepts

  • Streptomyces formicae