Engineering enzymatic assembly lines to produce new antibiotics

Curr Opin Microbiol. 2019 Oct:51:88-96. doi: 10.1016/j.mib.2019.10.007. Epub 2019 Nov 16.


Numerous important therapeutic agents, including widely-used antibiotics, anti-cancer drugs, immunosuppressants, agrochemicals and other valuable compounds, are produced by microorganisms. Many of these are biosynthesised by modular enzymatic assembly line polyketide synthases, non-ribosomal peptide synthetases, and hybrids thereof. To alter the backbone structure of these valuable but difficult to modify compounds, the respective enzymatic machineries can be engineered to create even more valuable molecules with improved properties and/or to bypass resistance mechanisms. In the past, many attempts to achieve assembly line pathway engineering failed or led to enzymes with compromised activity. Recently our understanding of assembly line structural biology, including an appreciation of the conformational changes that occur during the catalytic cycle, have improved hugely. This has proven to be a driving force for new approaches and several recent examples have demonstrated the production of new-to-nature molecules, including anti-infectives. We discuss the developments of the last few years and highlight selected, illuminating examples of assembly line engineering.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anti-Bacterial Agents / biosynthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacteria / enzymology
  • Bacteria / genetics
  • Bacteria / metabolism*
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Biocatalysis
  • Peptide Synthases / genetics*
  • Peptide Synthases / metabolism
  • Polyketide Synthases / genetics*
  • Polyketide Synthases / metabolism
  • Protein Engineering*


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Polyketide Synthases
  • Peptide Synthases
  • non-ribosomal peptide synthase