Antibiotic-free high-yield (-)-α-bisabolol production in Serratia marcescens via metabolic engineering and genomic integration of mevalonate pathway genes

(-)-α-Bisabolol, a valuable monocyclic sesquiterpene alcohol, has garnered significant attention in the pharmaceutical and cosmetic industries due to its remarkable anti-inflammatory, antibacterial, and skin-care properties. In this study, <i>Serratia marcescens</i> HBQA7 (<i>S. marcescens</i> HBQA7), a non-model strain resistant to terpenoid toxicity, was used as the production host, and the expression intensities of different integration sites were screened. The complete (-)-α-bisabolol synthesis pathway was integrated into these sites, achieving a production titer of 3.5 g L^-1. On this basis, by knocking out competitive pathway genes (such as <i>slaB</i> and <i>adhE</i>) and global regulatory factors (<i>arcA</i> and <i>iclR</i>), and introducing efficient glucose transport and activation (<i>glf</i> and <i>glk</i>), the shake flask fermentation titer was increased to 7.21 g L^-1. Through optimization of fermentation culture by orthogonal experiments and others, the titer was further increased to 9.90 g L^-1. Finally, through the fed-batch fermentation process conducted in a 50 L bioreactor, a titer of 102.3 g L^-1 was achieved after 110 h of cultivation. The productivity reached 0.93 g L^-1 h^-1. This study not only establishes the most efficient microbial production system for (-)-α-bisabolol reported to date, but also demonstrates the outstanding potential of <i>S. marcescens</i> as a chassis for terpenoid biosynthesis. It provides a novel strategy for the industrial production of high-value terpenoids.