Engineering of the Human Skin Bacterium Cutibacterium Acnes for Medical Applications

A prominent goal of synthetic biology is the development of living medicines based on engineered cells. The genetic modification of the human microbiome presents fewer risks for the host than the editing of human cells, and bacterial therapeutics have been employed to treat metabolic disorders, to limit cancer progression, or to address microbiome dysbiosis. In contrast to the numerous attempts to program gut bacteria for therapeutics, the engineering of the skin microbiome has remained largely unexplored despite its enormous potential.

Cutibacterium acnes, a bacterium that thrives within the sebaceous follicles, is the most abundant human skin microbe and has demonstrated promising engraftment properties when transplanted from a donor to a recipient individual. Despite being an ideal chassis for the development of living skin biotherapeutics, the engineering of C. acnes has long been hampered by the extremely low transformation efficiency and the lack of molecular biology tools available.

Here we reverted this situation and rendered C. acnes an engineerable chassis for skin disorders. First, we increased the transformability of C. acnes by several orders of magnitude. This paved the way for the generation of an engineering toolbox for C. acnes that includes modular plasmids and cloning schemes, a promoter library, a library of fluorescent reporters, and gene expression control tools such as CRISPRi and inducible transcription factors. The use of these tools enables the construction of synthetic gene circuits to control C. acnes behaviour in a programmable manner, and the development of strains that produce and secrete molecules with therapeutic potential.