Universal gene circuit boosts microbial production of 3-hydroxypropionic acid

Bacteria can be engineered as tiny factories to make useful chemicals. But as it needs to grow and produce at the same time, these two processes compete for resources. Traditional methods keep production genes always on, which puts a heavy burden on the bacteria, leading to poor growth and production. While dynamic regulation works like a timer, switching genes on at the right time, most earlier systems rely on signals from specific chemicals, so they are hard to use for different products.

To that end, a team led by Professors Quanfeng Liang and Qingsheng Qi at Shandong University used bacteria's natural "quorum sensing" and "stationary phase" signals to build a three-module automatic timer. “Simply put, when the number of bacteria is low, the first switch turns on; when they enter stationary phase, the second switch turns on; and a bit later, the third switch turns on,” explains Liang. “The three switches start at about 3, 5, and 9.5 hours, without adding any external inducers.”

The team published their findings in Engineering Microbiology.

“We used the system in E. coli to produce 3-hydroxypropionic acid (3-HP),” shares Qi. “Inside E. coli, two competing branches consume the raw materials. The three switches work together: one shuts down a branch that steals raw material, another opens the production line for 3-HP, and the third shuts down another competing branch.”

As a result, the shake-flask yield reached 7.0 g/L, 27% higher than the traditional method. Notably, the bacteria also grew better and consumed less sugar.

“The system is triggered by the bacteria's own state, not by a specific product,” says Liang. “To switch to a different target product, only the corresponding genes need to be replaced, allowing the bacteria to be quickly re-engineered.” 

The team also found that more switches are not always better: a two-module strain grew and produced less. “If the strength or timing of the switches is wrong, it can harm the bacteria, indicating that metabolic regulation is complex and needs careful optimization,” says Qi. “This work provides a universal tool for microbial cell factories.”

Contact the author:

Quanfeng Liang

State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China

Email: liangquanfeng@sdu.edu.cn

Funder:

This work was supported by the National Key R&D Program of China (No. 2024YFC3407100), the National Key Research and Development Program of China (2024YFC3407100), the National Natural Science Foundation of China (32470065), Hainan Province Science and Technology Special Fund (No. ZDYF2024XDNY164) and SKLMT Frontiers and Challenges Project (SKLMTFCP-2023-03).

Conflict of interest:

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

See the article:

Gao, Y., et al., Construction of a pathway-independent three-module self-induced regulatory system and its application in 3-hydroxypropionic acid production, Engineering Microbiology, 6(1), 2026, 100281, https://doi.org/10.1016/j.engmic.2026.100281.