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

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...

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Bibliographic Details
Published in:ACS synthetic biology 2021-10, Vol.10 (10), p.2520-2531
Main Authors: Li, Yiwei, Reed, Megan, Wright, H. Tonie, Cropp, T. Ashton, Williams, Gavin J
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - biosynthesis
Anti-Bacterial Agents - chemistry
Biosensing Techniques - methods
Macrolides - chemistry
Macrolides - metabolism
Methyltransferases - metabolism
Molecular Structure
Mutagenesis
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Summary: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.
ISSN:2161-5063
2161-5063
DOI:10.1021/acssynbio.1c00151