CUTISKIN · CUtibacterium acnes metabolic engineering for Therapeutic Indole in situ delivery in atopic dermatitis SKIN

Atopic dermatitis (AD), also known as eczema, affects more than 125 million people worldwide. This disease severely impacts patient quality of life and generates annual healthcare costs exceeding 30€ billion in Europe. The skin microbiome represents a promising dynamic delivery system for the treatment of AD. Notably, Cutibacterium acnes, the most abundant skin commensal, has preferential colonization of the hair follicles and high engraftment when applied topically in the skin. However, current engineering of this bacterium is limited to proteins, which diffuse poorly across the skin. CUTISKIN aims to pioneer the metabolic engineering of C. acnes for the dynamic production of therapeutic small molecules against AD. It will (i) develop a multiplex genome engineering method for C. acnes to enable high-throughput pathway integration; (ii) build a genome-scale metabolic model (GEM) constrained to skin physiology to optimize metabolite production; and (iii) establish a methodology to evaluate therapeutic effect in advanced 3D skin models of AD. This interdisciplinary project combines synthetic biology, metabolic modelling, and dermatology, representing the first attempt to metabolically reprogram a skin commensal for therapeutic metabolite delivery. Furthermore, it will establish a metabolic platform adaptable to other skin disorders and develop methods expandable to other non-model organisms, advancing microbiome therapeutics in Europe.