Enhanced Bioproduction and Processing of Mandelic Acid Enantiomers: Towards a Sustainable Platform for High-value Pharmaceutical and Polymer Applications

Background: Mandelic acid (MA) is a high-value chiral platform molecule with broad applications in pharmaceutical synthesis, cosmetic formulations, and polymer production. Conventional chemical synthesis is limited by harsh reaction conditions, poor enantioselectivity, and environmental concerns. Microbial biosynthesis offers a sustainable and stereoselective alternative; however, its industrial application is constrained by low titres, suboptimal productivity, and inefficient downstream recovery. This study reports an engineered microbial chassis that enables enhanced biosynthesis of MA enantiomers with integrated downstream compatibility. Results: The biosynthetic potential of Escherichia coli was harnessed through targeted metabolic engineering and pathway optimisation for the biosynthesis of ( R )- and ( S )-MA. Batch fermentations in rich medium produced 1.6 g/L ( R )-MA and 1.8 g/L ( S )-MA. Transitioning to fed-batch cultivation in defined minimal medium, under non-optimised conditions, increased titres to 2.9 g/L; ee  = 99% for ( R )-MA and 5.7 g/L; ee  = 93% for ( S )-MA, representing the highest reported in vivo titres of MA enantiomers achieved in E. coli to date. A two-step downstream process comprising solvent extraction and crystallisation enabled the recovery of MA at high purity (> 99.0%), with recovery efficiencies of 84% for ( S )-MA and 77% for ( R )-MA. To validate the functional utility of bio-based MA, SAMMA, a sulfuric acid condensation polymer with documented antiviral and contraceptive properties, was synthesised from both bio-based and commercial MA. Additionally, mandelide, a monomer precursor for the biodegradable polystyrene analogue polymandelide (PM), was synthesised to illustrate the platform’s relevance to sustainable polymer applications. Conclusions: This study establishes a robust proof of concept for a microbial platform enabling enantioselective MA biosynthesis from renewable carbon source. Through the integration of metabolic engineering, downstream process development and application-driven validation, this platform lays the foundation for a scalable and industrially relevant bioproduction strategy. Aligned with the principles of green chemistry and the circular bioeconomy, this approach offers a sustainable and environmentally responsible route to high-value chiral chemicals.