Mixing and matching genes of marine and terrestrial origin in the biosynthesis of the mupirocin antibiotics. Issue 20 (9th May 2020)

• Record Type: Journal Article
• Authors: Wang, Luoyi; Song, Zhongshu; Race, Paul R.; Spencer, James; Simpson, Thomas J.; Crump, Matthew P.; Willis, Christine L.
• Is Part Of: Chemical science. Volume 11:Issue 20(2020)
• Page Start: 5221
• Page End: 5226
• Publication Date: 2020-05-09
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c9sc06192d
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Where the sea meets the land: the mupirocin biosynthetic gene cluster (BGC) from the terrestrial bacterium Pseudomonas fluorescens was repurposed via a plug-and-play approach with heterologous genes from the marine strain that produces thiomarinol. 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.