Clavulanic acid (CA) is an irreversible β-lactamase enzyme inhibitor with a weak antibacterial activity produced by Streptomyces clavuligerus (S. clavuligerus). CA is typically co-formulated with broad-spectrum β‑lactam antibiotics such as amoxicillin, conferring them high potential to treat diseases caused by bacteria that possess β‑lactam resistance. The clinical importance of CA and the complexity of the production process motivate improvements from an interdisciplinary standpoint by integrating metabolic engineering strategies and knowledge on metabolic and regulatory events through systems biology and multi-omics approaches. In the large-scale bioprocessing, optimization of culture conditions, bioreactor design, agitation regime, as well as advances in CA separation and purification are required to improve the cost structure associated to CA production. This review presents the recent insights in CA production by S. clavuligerus, emphasizing on systems biology approaches, strain engineering, and downstream processing.

中文翻译：

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棒链霉菌生产克拉维酸：来自系统生物学、菌株工程和下游加工的见解

克拉维酸（CA）是由棒状链霉菌（S. clavuligerus）产生的一种不可逆的β-内酰胺酶抑制剂，具有弱抗菌活性。CA 通常与阿莫西林等广谱 β 内酰胺抗生素共同配制，赋予它们治疗由具有 β 内酰胺耐药性的细菌引起的疾病的巨大潜力。CA 的临床重要性和生产过程的复杂性通过系统生物学和多组学方法整合代谢工程策略和代谢和调节事件知识，从跨学科的角度推动了改进。在大规模生物加工中，需要优化培养条件、生物反应器设计、搅拌方式以及 CA 分离和纯化方面的进步，以改善与 CA 生产相关的成本结构。这篇综述介绍了S. clavuligerus生产 CA 的最新见解，重点是系统生物学方法、菌株工程和下游加工。