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Development of stable platform strains for improved clavulanic acid production

Project Description

Project Description: (Max 2000 characters including spaces)
Streptomycetes possess a single chromosome, but unlike in other bacteria, it is linear with Terminal Inverted Repeats (TIRs) of up to 1mbp in size; in addition, most streptomycetes have Giant linear Plasmids (GLPs). The founder strain for manufacture of the antibiotics, clavulanic acid (CA) is Streptomyces clavuligerus (Sclav) that has been sequenced in a draft form by next generation sequencing (NGS) several times and consists of a ~6.8 Mb chromosome, including the CA biosynthetic gene cluster, and four GLPs. However there are significant discrepancies between these sequences, especially in the size and location of the GLPs due to the inability of NGS to detect TIRs and resolve chromosomal integration of the GLPs. As a result, the TIRs, as well as the size and location of the GLPs, have not been accurately mapped; this is an essential prerequisite for the knowledge-led improvement of CA productivity by Sclav. The aim of this project is to generate an accurate map of the genome of Sclav and to deliver strains with improved stability, fermenter performance and clavulanic acid productivity. We will do this by carrying out physical and genomic analysis of strains at Strathclyde and then characterise advanced production strains in the same way at GSK. This will provide a firm foundation for the generation of enhanced production strains by GSK for improved CA productivity. Armed with this information, we will then systematically cure GLPs from Sclav strains, where it is possible to do so, and assaying for improved CA production, develop stable platform strains for GSK. Thus the student will gain experience in both an academic and the industrial laboratory setting.

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