Continuous bioactivity-dependent evolution of an antibiotic biosynthetic pathway

Nat Commun. 2020 Aug 21;11(1):4202. doi: 10.1038/s41467-020-18018-2.


Antibiotic biosynthetic gene clusters (BGCs) produce bioactive metabolites that impart a fitness advantage to their producer, providing a mechanism for natural selection. This selection drives antibiotic evolution and adapts BGCs for expression in different organisms, potentially providing clues to improve heterologous expression of antibiotics. Here, we use phage-assisted continuous evolution (PACE) to achieve bioactivity-dependent adaptation of the BGC for the antibiotic bicyclomycin (BCM), facilitating improved production in a heterologous host. This proof-of-principle study demonstrates that features of natural bioactivity-dependent evolution can be engineered to access unforeseen routes of improving metabolic pathways and product yields.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / biosynthesis*
  • Biological Products / metabolism
  • Biosynthetic Pathways / genetics*
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism
  • Cloning, Molecular
  • Escherichia coli
  • Gene Expression Regulation, Bacterial
  • Metabolic Engineering
  • Multigene Family*
  • Pseudomonas fluorescens / genetics
  • Pseudomonas fluorescens / metabolism


  • Anti-Bacterial Agents
  • Biological Products
  • Bridged Bicyclo Compounds, Heterocyclic
  • bicozamycin