Understanding genome dynamics of Streptomyces clavuligerus during industrial fermentations

The rise of Antimicrobial Resistant (AMR) Infections means that a greater understanding of antibiotic production and strain development for industrial processes is required to safeguard current production and to accelerate delivery of new molecules to market. Clavulanic acid (CA) is produced by Streptomyces clavuligerus and is a co-formulated with amoxicillin (The GSK product is Augmentin). This co-formulation is a member of the WHO 'Essential Medicines' list and is used for community-acquired infections. Industrial antibiotic production by Streptomyces in submerged fermentation is optimised by balancing nutrients, growth rate, and the environment to which cells are exposed. A key component of production at scale is the optimised Streptomyces strain used in the process. The cellular output is traditionally improved through selection of higher-producing strains following random mutagenesis combined with fermentation optimisation. The current CA producing strain and process has evolved at GSK through incremental and empirical steps for >30 years and has used many production strains. The patent for this co-formulation has expired and as such, this proprietry knowledge and the high-performing production strains are key to a profitable process. The strain improvement is on-going, with new production strains continuosly being evaluated. Recently we have learned from genome-sequencing efforts that the genome of S. clavuligerus is much more dynamic than previously thought, suggesting that strains may undergo genome rearrangements during sub-culture and fermentation that have profound effects on CA production. To exploit these data in a timely manner, we will addresses key questions from GSK in terms of their industrial fermentation. Why do serial sub-cultures lose productivity? Why does the efficiency of CA production decline over the lifetime of the fermentation? What triggers the end of the fermentation process? Addressing these questions for the Augmentin process will enable us to gain a deeper understanding of genome dynamics of S. clavuligerus during production. This understanding is key to GSK maintaining market position and for the development of future strains.