Constructing High-Yielding <i>Serratia marcescens</i> for (−)-α-Bisabolol Production Based on the Exogenous Haloarchaeal MVA Pathway and Endogenous Molecular Chaperones

(-)-α-Bisabolol exhibits analgesic, anti-inflammatory, and skin-soothing properties and is widely applied in the cosmetic and pharmaceutical industries. The use of plant essential oil distillation or chemical synthesis to produce (-)-α-bisabolol is both inefficient and unsustainable. Currently, the microbial production of (-)-α-bisabolol mainly relies on <i>Escherichia coli</i> and <i>Saccharomyces cerevisiae</i> as chassis strains; however, high concentrations of (-)-α-bisabolol have certain toxicity to the strain. This study uses synthetic biology and metabolic engineering strategies to redesign a solvent-tolerant <i>Serratia marcescens</i> for the efficient production of (-)-α-bisabolol. By introducing the Haloarchaea-type mevalonate (MVA) pathway and the (-)-α-bisabolol biosynthesis pathway, we successfully constructed a strain capable of producing (-)-α-bisabolol. The coexpression of the chaperone protein DnaK/J significantly enhanced the soluble expression of the (-)-α-bisabolol synthase, resulting in a 10% increase in (-)-α-bisabolol titer. Furthermore, knockout of the <i>PhoA</i> gene, which reduced the formation of the byproduct farnesol (FOH), further increased the (-)-α-bisabolol titer to 3.21 g/L. In a 5 L bioreactor, <i>S. marcescens</i> achieved a final (-)-α-bisabolol titer of 30.2 g/L, representing the highest titer reported to date. This research provides guidance for the production of (-)-α-bisabolol in nonmodel microorganisms without the requirement for induction.