Moving Hyaluronic Acid Production away from Rooster Combs and Pathogenic Bacteria

Hyaluronic acid (HA) is an important high-molecular weight biopolymer that plays critical roles in lubricating connective tissues of the musculo-skeletal system and in skin repair. As a long glycosaminoglycan with non-immunogenic and non-toxic attributes as well as excellent moisture-retention and viscoelastic properties, HA is used in products ranging from viscosupplements that are injected into the knee joints of patients with osteoarthritis, to injectable dermal fillers in cosmetic procedures, to skin moisturizers and dietary supplements. With such broad relevance across the healthcare, cosmetic and food industries, it is unsurprising that the market for industrially-produced HA is estimated at over $7 billion, with demand for this biocompatible molecule expected to exceed $15 billion by 2025.

HA was originally extracted from rooster combs, but due to high production costs and health concerns associated with animal-derived HA, focus shifted to generating HA via microbial fermentation of group C streptococci. However, Streptococcus sp. are pathogenic and do not meet the Generally Recognized as Safe (GRAS) designation for organisms by the United States Food and Drug Administration (U.S. FDA). Concerns that HA produced by streptococcal fermentation may contain bacterial exotoxins motivated the use an alternative non-pathogenic bacterial strain, Bacillus subtilis, to industrially produce HA. B. subtilis is a robust, gram-positive bacteria that possesses GRAS status, favoring them for use in the industrial production of biological products like proteins and biopolymers. Importantly, Westbrook et al. (2018) developed a way to increase HA production in B. subtilis by using CRISPRi to strategically downregulate the expression of two metabolic enzymes, pfkA and zwf. Both these enzymes play roles in funneling carbon into the glycolysis, cell wall synthesis, and pentose phosphate pathways. By reducing the expression of these enzymes, carbon passage was redirected toward HA biosynthesis, doubling the amount of HA produced compared to the control strain.

Being able to genetically manipulate B. subtilis to increase heterologous HA production is an exciting development, especially as demand for HA continues to increase. This study also highlights the versatile, cost-effective, high-yielding nature of B. subtilis expression, and how advancements in genetic engineering have made B. subtilis more amenable to the production of a wider variety proteins.

Interested in giving protein expression in B. subtilis a try? GenScript now offers a new option for customized protein expression in B. subtilis. Let GenScript’s experts work with you to achieve your desired protein expression goal. Click here to learn more!

Westbrook, A. W., Ren, X., Oh, J., Moo-Young, M. & Chou, C. P. Metabolic engineering to enhance heterologous production of hyaluronic acid in Bacillus subtilis. Metab. Eng. (2018).

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