Cutibacterium acnes inhibits Staphylococcus lugdunensis biofilm formation through inhibition of autolysis and purine biosynthesis.

Cutibacterium acnes is a key member of the human skin microbiome that contributes to host homeostasis. Staphylococcus lugdunensis, while also a resident of the skin microbiota, is an opportunistic pathogen capable of causing severe infections, associated with its ability to form biofilms. We previously showed that C. acnes secretes molecules that inhibit S. lugdunensis biofilm formation without affecting planktonic growth. Here, we demonstrate that C. acnes-derived molecules also significantly reduced S. lugdunensis adherence to and invasion of human epithelial cells, as well as adhesion to keratinocytes. Transcriptomic analysis revealed repression of genes involved in S. lugdunensis purine biosynthesis and induction of the autolysis negative regulators, lrgA and lrgB. Functional assays confirmed that exposure to C. acnes molecules inhibits autolysis and extracellular DNA (eDNA) release and decreases intracellular guanine levels in S. lugdunensis. Crucially, the addition of exogenous guanine suppressed the effect of C. acnes molecules on both biofilm formation and lrgA gene expression. Collectively, our data indicate that C. acnes molecules inhibit S. lugdunensis biofilm formation by depleting the intracellular guanine pool, leading to repression of autolysis, and reduced eDNA release, a key component of biofilm structural integrity. These findings underscore the importance of interspecies microbiome interactions in pathogen exclusion.