Current microbial cell factory methods for producing chemicals from renewable resources primarily rely on (fed‐)batch production systems, leading to the accumulation of the desired product. Industrially relevant chemicals like 2‐phenylethanol (2PE), a flavor and fragrance compound, can exhibit toxicity at low concentrations, inhibit the host activity, and negatively impact titer, rate, and yield. Batch liquid‐liquid (L‐L) In Situ Product Removal (ISPR) was employed to mitigate inhibition effects, but was not found sufficient for industrial‐scale application. Here, we demonstrated that continuous selective L‐L ISPR provides the solution for maintaining the productivity of de novo produced 2PE at an industrial pilot scale. A unique bioreactor concept called “Fermentation Accelerated by Separation Technology” (FAST) utilizes hydrostatic pressure differences to separate aqueous‐ and extractant streams within one unit operation, where both production and product extraction take place ‐ allowing for the control of the concentration of the inhibiting compound. Controlled aqueous 2PE levels (0.43 ± 0.02 g kg−1) and extended production times (>100 h) were obtained and co‐inhibiting by‐product formation was reduced, resulting in a twofold increase of the final product output of batch L‐L ISPR approaches. This study establishes that continuous selective L‐L ISPR, enabled by FAST, can be applied for more economically viable production of inhibiting products.

中文翻译：

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通过连续萃取发酵进行抑制控制可增强酵母从头 2-苯乙醇的生产


目前从可再生资源中生产化学品的微生物细胞工厂方法主要依赖于（补料-）批量生产系统，从而积累所需的产品。2-苯乙醇 （2PE） 是一种香精香料化合物，等工业相关化学品在低浓度下可能表现出毒性，抑制宿主活性，并对滴度、速率和产量产生负面影响。采用批量液-液 （L-L） 原位产物去除 （ISPR） 来减轻抑制作用，但未发现足以用于工业规模应用。在这里，我们证明了连续选择性 L-L ISPR 为在工业中试规模上保持从头生产的 2PE 的生产率提供了解决方案。一种称为“分离技术加速发酵”（FAST） 的独特生物反应器概念利用静水压力差在一个单元操作中分离水流和萃取剂流，同时进行生产和产品提取，从而可以控制抑制化合物的浓度。获得了受控的 2PE 水溶液水平 （0.43 ± 0.02 g kg-1） 和延长的生产时间 （>100 h），减少了共抑制副产物的形成，导致批次 L-L ISPR 方法的最终产品产量增加了两倍。本研究确定，由 FAST 实现的连续选择性 L-L ISPR 可用于更经济可行的抑制产物生产。