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Issue 20, 2020

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

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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 applications than mupirocin.

Graphical abstract: Mixing and matching genes of marine and terrestrial origin in the biosynthesis of the mupirocin antibiotics

Supplementary files

Article information


Submitted
06 Dec 2019
Accepted
29 Apr 2020
First published
09 May 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 5221-5226
Article type
Edge Article

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

L. Wang, Z. Song, P. R. Race, J. Spencer, T. J. Simpson, M. P. Crump and C. L. Willis, Chem. Sci., 2020, 11, 5221 DOI: 10.1039/C9SC06192D

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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