Ectoine, also known as 1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid is an amino acid derivative and compatible solute (Galinski et al., 1985; Inbar et al., 1993; Inbar and Lapidot, 1988). Due to its structural characteristics, ectoine shows strong capability to bind water, which can well balance osmotic pressure inside and outside cells (Barth et al., 2000; Da Costa et al., 1998; Dubencovs et al., 2022; Galinski and Trüper, 1994; Gunde-Cimerman et al., 2018; Kurz, 2008; León et al., 2018; Zaccai et al., 2016). Furthermore, ectoine can help stabilize the structure of proteins and macromolecules, which can moisturize and protect the skin from oxidative damage and aging (Berneburg et al., 1997; Botta et al., 2008; Buenger and Driller, 2004; Buommino et al., 2005; Grether-Beck et al., 2005; Heinrich et al., 2007; Knapp et al., 1999; Kurz, 2008; Zaccai et al., 2016). Furthermore, it can assist microorganisms in resisting various stresses such as salinity and extreme temperature (Fig. 1) (León et al., 2018; Pastor et al., 2010; Reuter et al., 2010; Schwibbert et al., 2011). In addition, ectoine can protect ileal mucosa and muscularis against cold ischemia and subsequent warm in vitro reperfusion injury (Aguzzi and Polymenidou, 2004; Furusho et al., 2005; Kanapathipillai et al., 2008; Sydlik et al., 2009; Wei et al., 2009). Owing to its wide applications in cosmetics, medicine and other fields, the annual demand for ectoine is about 15,000 tons with the market size of billions of dollars (around 1000 dollars/kg) (Kunte et al., 2014).

Currently, ectoine has been industrially produced through either chemical synthesis or biological fermentation (Kunte et al., 2014; Li et al., 2021; Strong et al., 2016). However, chemical synthesis has shown several disadvantages including long reaction steps, low yield, poor stereoselectivity and high cost (Kunte et al., 2014). In contrast, as a more environmentally friendly process, the biological fermentation shows high advantages of stereoselectivity and regioselectivity (Kunte et al., 2014; Pastor et al., 2010). Currently, the microbial fermentation is the most preferred method for ectoine production (Kunte et al., 2014). The biosynthesis of ectoine generally involves in three steps: L-2,4-diaminobutyrate transaminase (EctB) first converts aspartate semialdehyde to L-2,4-diaminobutyric acid via transamination of glutamate, while diaminobutyrate acetyl transferase (EctA) then acetylates L-2,4-diaminobutyric acid with acetyl-CoA to N-acetyl-L-2,4-diaminobutyric acid and ectoine synthase (EctC) finally cyclizes N-acetyl-L-2,4-diaminobutyric acid to ectoine.

In nature, some ectoine producing strains such as Halomonas sp. have been successfully isolated and used for ectoine production, however, the production efficiency was still low. With the rapid development of synthetic biology and fermentation engineering, many strategies have been developed to improve the ectoine production and simplify the production process. For example, some model microorganisms such as Escherichia coli and Corynebacterium glutamicum have been genetically modified to achieve high ectoine production. Moreover, different low cost substrates have also been adopted for ectoine production to further decrease the production costs. Accordingly, this review will comprehensively summarize the recent advances on ectoine production by using different microorganism hosts. Different process parameters affecting the ectoine production efficiency will be evaluated, and future prospects were also proposed.