Development of Genetically Encoded Biosensors for Reporting the Methyltransferase-Dependent Biosynthesis of Semisynthetic Macrolide Antibiotics

ACS Synth Biol. 2021 Oct 15;10(10):2520-2531. doi: 10.1021/acssynbio.1c00151. Epub 2021 Sep 21.


Clarithromycin is an improved semisynthetic analogue of the naturally occurring macrolide, erythromycin. The subtle modification of a methyl group on the C-6 hydroxyl group endows the molecule with improved acid stability and results in a clinically useful antibiotic. Here, we show that the effector specificity of the biosensor protein, MphR, can be evolved to selectively recognize clarithromycin and therefore report on the production of this molecule in vivo. In addition, a crystal structure of the evolved variant reveals the molecular basis for selectivity and provides a guide for the evolution of a new metabolic function using this biosensor.

Keywords: biosensor; macrolide; polyketide; synthetic biology; transcription factor.

Publication types

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

MeSH terms

  • Anti-Bacterial Agents / biosynthesis*
  • Anti-Bacterial Agents / chemistry
  • Biosensing Techniques / methods*
  • Macrolides / chemistry
  • Macrolides / metabolism*
  • Methyltransferases / metabolism*
  • Molecular Structure
  • Mutagenesis


  • Anti-Bacterial Agents
  • Macrolides
  • Methyltransferases