Advanced DNA synthesis, biosensor assembly, and genetic circuit development in synthetic biology and metabolic engineering have reinforced the application of filamentous bacteria, yeasts, and fungi as promising chassis cells for chemical production, but their industrial application remains a major challenge that needs to be solved.As important chassis strains, filamentous microorganisms can synthesize important enzymes, chemicals, and niche pharmaceutical products through microbial fermentation. With the aid of metabolic engineering and synthetic biology, filamentous bacteria, yeasts, and fungi can be developed into efficient microbial cell factories through genome engineering, pathway engineering, tolerance engineering, and microbial engineering. Mutant screening and metabolic engineering can be used in filamentous bacteria, filamentous yeasts (Candida glabrata, Candida utilis), and filamentous fungi (Aspergillus sp., Rhizopus sp.) to greatly increase their capacity for chemical production. This review highlights the potential of using biotechnology to further develop filamentous bacteria, yeasts, and fungi as alternative chassis strains.In this review, we recapitulate the recent progress in the application of filamentous bacteria, yeasts, and fungi as microbial cell factories. Furthermore, emphasis on metabolic engineering strategies involved in cellular tolerance, metabolic engineering, and screening are discussed. Finally, we offer an outlook on advanced techniques for the engineering of filamentous bacteria, yeasts, and fungi. 

/pdf/microbial-cell-factories-based-on-filamentous-bacteria-1t53kspv.pdf

Microbial cell factories based on filamentous bacteria, yeasts, and fungi

Biosensor-assisted titratable CRISPRi high-throughput (BATCH) screening for over-production phenotypes.

Bioplastics are polymers made from sustainable bio-based feedstocks. While the potential of producing bio-based monomers in microbes has been investigated for decades, their economic feasibility is still unsatisfactory compared with petroleum-derived methods. To improve the overall synthetic efficiency of microbial cell factories, three main strategies were summarized in this review: firstly, implementing approaches to improve the microbial utilization ability of cheap and abundant substrates; secondly, developing methods at enzymes, pathway, and cellular levels to enhance microbial production performance; thirdly, building technologies to enhance microbial pH, osmotic, and metabolites stress tolerance. Moreover, the challenges of, and some perspectives on, exploiting microorganisms as efficient cell factories for producing bio-based monomers are also discussed.

/pdf/engineering-microorganisms-to-produce-bio-based-monomers-3uiaohc9.pdf

Engineering Microorganisms to Produce Bio-Based Monomers: Progress and Challenges

L-malic acid (L-MA) is an important intermediate in the tricarboxylic acid cycle and a crucial bulk chemical with various applications in the food, pharmaceutical, and chemical industries. With the rapid advancements in metabolic engineering technology and the global commitment toward fostering a green economy and sustainable development, the large-scale production of L-MA is gradually transitioning from conventional petroleum-based approaches to microbial fermentation. This comprehensive review aims to provide a thorough overview of the historical background and recent advancements in the microbial fermentation production of L-MA, encompassing an in-depth introduction to diverse biosynthetic pathways and host strains. Moreover, this review elucidates the challenges encountered in the industrialization of microbial fermentation production of L-MA, offering a summary of potential solutions and prospects for future research directions. The anticipated outcome of this review is to contribute valuable theoretical guidance toward promoting technological innovation in L-MA production. 

Microbial L-malic acid production: History, current progress, and perspectives

Increasing attention is being focused on using lignocellulose for valuable products. Microbial decomposition can convert lignocellulose into renewable biofuels and other high-value bioproducts, contributing to sustainable development. However, the presence of inhibitors in lignocellulosic hydrolysates can negatively affect microorganisms during fermentation. Improving microbial tolerance to these hydrolysates is a major focus in metabolic engineering. Traditional detoxification methods increase costs, so there is a need for cheap and efficient cell-based detoxification strategies. Synthetic biology approaches offer several strategies for improving microbial tolerance, including redox balancing, membrane engineering, omics-guided technologies, expression of protectants and transcription factors, irrational engineering, cell flocculation, and other novel technologies. Advances in molecular biology, high-throughput sequencing, and artificial intelligence (AI) allow for precise strain modification and efficient industrial production. Developing AI-based computational models to guide synthetic biology efforts and creating large-scale heterologous libraries with automation and high-throughput technologies will be important for future research.

Synthetic biology approaches to improve tolerance of inhibitors in lignocellulosic hydrolysates

Microbial cell factories offer an economic and environmentally friendly method for the biosynthesis of acetyl-CoA-derived chemicals. However, the static control of carbon flux can cause direct and indirect competition for acetyl-CoA between cell growth and chemical biosynthesis, limiting the efficiency of microbial cell factories. Herein, recombinase-based genetic circuits were developed to achieve the optimal distribution of acetyl-CoA between cell growth and butyrate biosynthesis. First, three dynamic devices-a turn-on switch, a turn-off switch, and a recombinase-based inverter (RBI)-were constructed based on Bxb1 recombinase. Then, the turn-on switch was used to dynamically control the butyrate biosynthetic pathway, which directly improved the consumption of acetyl-CoA. Next, the turn-off switch was applied to dynamically control cell growth, which indirectly enhanced the supply of acetyl-CoA. Finally, an RBI was adopted for the dynamic dual control of the distribution of acetyl-CoA between cell growth and butyrate biosynthesis. The final butyrate production rate was increased to 34 g/L, with a productivity of 0.405 g/L/h. The strategy described herein will pave the way for the development of high-performance microbial cell factories for the production of other desirable chemicals. KEY POINTS: • Competition for acetyl-CoA between cell growth and synthesis limits productivity. • Recombinase-based genetic circuits were developed to dynamic control of acetyl-CoA. • Optimal distribution of acetyl-CoA between cell growth and synthesis was achieved.

Dynamic control of the distribution of carbon flux between cell growth and butyrate biosynthesis in Escherichia coli

Microbial cell factories provide a sustainable and economical way to produce chemicals from renewable feedstocks. However, the accumulation of targeted chemicals can reduce the robustness of the industrial strains and affect the production performance. Here, the physiological functions of Mediator tail subunit CgMed16 at l-malate stress were investigated. Deletion of CgMed16 decreased the survival, biomass, and half-maximal inhibitory concentration (IC50 ) by 40.4%, 34.0%, and 30.6%, respectively, at 25 g/L l-malate stress. Transcriptome analysis showed that this growth defect was attributable to changes in the expression of genes involved in lipid metabolism. In addition, tolerance transcription factors CgUSV1 and CgYAP3 were found to interact with CgMed16 to regulate sterol biosynthesis and glycerophospholipid metabolism, respectively, ultimately endowing strains with excellent membrane integrity to resist l-malate stress. Furthermore, a dynamic tolerance system (DTS) was constructed based on CgUSV1, CgYAP3, and an l-malate-driven promoter Pcgr-10 to improve the robustness and productive capacity of C. glabrata. As a result, the biomass, survival, and membrane integrity of C. glabrata 012 (with DTS) increased by 22.6%, 31.3%, and 53.8%, respectively, compared with those of strain 011 (without DTS). Therefore, at shake-flask scale, strain 012 accumulated 35.5 g/L l-malate, and the titer and productivity of l-malate increased by 32.5% and 32.1%, respectively, compared with those of strain 011. This study provides a novel strategy for the rational design and construction of DTS for dynamically enhancing the robustness of industrial strains. This article is protected by copyright. All rights reserved.

Dynamic regulation of membrane integrity to enhance l-malate stress tolerance in Candida glabrata.

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Dynamic control of the distribution of carbon flux between cell growth and butyrate biosynthesis in Escherichia coli

Dynamic regulation of membrane integrity to enhance l-malate stress tolerance in Candida glabrata.