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

Lookup NU author(s): Professor Paul RaceORCiD


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© The Royal Society of Chemistry 2020. 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 marinePseudoalternomonassp. producing thiomarinol can be expressed in functional form in the biosynthesis of the clinically important antibiotic mupirocin from the soil bacteriumPseudomonas 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-epoxyversus10,11-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.

Publication metadata

Author(s): Wang L, Song Z, Race PR, Spencer J, Simpson TJ, Crump MP, Willis CL

Publication type: Article

Publication status: Published

Journal: Chemical Science

Year: 2020

Volume: 11

Issue: 20

Pages: 5221-5226

Online publication date: 09/05/2020

Acceptance date: 29/04/2020

ISSN (print): 2041-6520

ISSN (electronic): 2041-6539

Publisher: Royal Society of Chemistry


DOI: 10.1039/c9sc06192d


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