Understanding genome dynamics of Streptomyces clavuligerus during industrial fermentations

抗菌素耐药性(AMR)感染的增加意味着需要更多地了解工业过程中的抗生素生产和菌株开发，以保护当前的生产并加快新分子向市场的交付。克拉维酸(CA)是由棒状链霉菌(Streptomyces Clavuligerus)产生的，是与阿莫西林(GSK产品为Augentin)的共同配方。这种联合制剂是世卫组织“基本药物”清单的成员之一，用于社区获得性感染。通过平衡营养、生长速度和细胞暴露的环境，链霉菌在深层发酵中生产工业抗生素是优化的。规模化生产的一个关键组成部分是工艺中使用的优化链霉菌菌株。传统上，细胞产量是通过随机诱变和发酵优化相结合的方式选择高产菌株来提高的。目前的CA生产菌株和工艺在葛兰素史克经过30年的循序渐进和经验步骤发展而来，并使用了许多生产菌株。这种联合配方的专利已经到期，因此，这种专有知识和高性能的生产菌株是有利可图的过程的关键。菌株改良正在进行中，新的生产菌株正在不断地进行评估。最近，我们从基因组测序工作中了解到，棒状葡萄球菌的基因组比以前认为的更具活力，这表明菌株在继代培养和发酵过程中可能会经历基因组重排，这对CA的产生有深远的影响。为了及时利用这些数据，我们将解决葛兰素史克在工业发酵方面的关键问题。为什么连续亚文化会失去生产力？为什么在整个发酵过程中，CA的生产效率会下降？是什么触发了发酵过程的结束？为Augentin过程解决这些问题将使我们能够更深入地了解棒状链霉菌生产过程中的基因组动态。这一认识是葛兰素史克保持市场地位和发展未来品系的关键。

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.