Mixing and matching genes of marine and terrestrial origin in the biosynthesis of the mupirocin antibiotics.

Chemical Science
Luoyi WangChristine L Willis

Abstract

With growing understanding of the underlying pathways of polyketide biosynthesis, along with the continual expansion of the synthetic biology toolkit, it is becoming possible to rationally engineer and fine-tune the polyketide biosynthetic machinery for production of new compounds with improved properties such as stability and/or bioactivity. However, engineering the pathway to the thiomarinol antibiotics has proved challenging. Here we report that genes from a marine Pseudoalternomonas sp. producing thiomarinol can be expressed in functional form in the biosynthesis of the clinically important antibiotic mupirocin from the soil bacterium Pseudomonas fluorescens. It is revealed that both pathways employ the same unusual mechanism of tetrahydropyran (THP) ring formation and the enzymes are cross compatible. Furthermore, the efficiency of downstream processing of 10,11-epoxy versus 10,11-alkenic metabolites are comparable. Optimisation of the fermentation conditions in an engineered strain in which production of pseudomonic acid A (with the 10,11-epoxide) is replaced by substantial titres of the more stable pseudomonic acid C (with a 10,11-alkene) pave the way for its development as a more stable antibiotic with wider application...Continue Reading

References

Aug 1, 1995·The Journal of Antibiotics·H ShiozawaS Takahashi
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May 14, 2010·Natural Product Reports·Jörn Piel
Mar 15, 2014·Journal of the American Chemical Society·Shu-Shan GaoChristine L Willis
Aug 19, 2015·Nature Chemical Biology·Eunji KimYeo Joon Yoon
Oct 23, 2015·Nature Protocols·Laura R HmeloJoe J Harrison
Dec 23, 2015·Natural Product Reports·Eric J N Helfrich, Jörn Piel
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Aug 10, 2016·Cold Spring Harbor Perspectives in Biology·Rainer Breitling, Eriko Takano
Jan 11, 2018·Synthetic and Systems Biotechnology·Jesus F BarajasJay D Keasling

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Citations

Aug 14, 2020·Natural Product Reports·Robert A Hill, Andrew Sutherland
Aug 4, 2021·Journal of the American Chemical Society·Rachel A JohnsonBo Li

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Methods Mentioned

BETA
gene knock-out
NMR
PCR

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