Oleum cinnamomi disrupts Cutibacterium acnes adhesion and metabolism by covalently targeting enolase and coenzyme A.

BACKGROUND: Preventing Cutibacterium acnes (C. acnes) adhesion to human skin is essential for acne control, yet the molecular determinants of adhesion-associated drug resistance remain undefined and no pharmacological agents specifically blocking C. acnes attachment are available. OBJECTIVE: To evaluate oleum cinnamomi (OC), a natural cinnamon oil, as a potential anti-adhesive modality against C. acnes. METHODS: In vitro antibacterial assays, quantitative chemoproteomics, and keratinocyte infection models were integrated to quantify OC-mediated inhibition of C. acnes adhesion and biofilm formation, map covalent targets of OC electrophiles cinnamaldehyde (CA) and 2-methoxycinnamaldehyde (MCA), and delineate downstream metabolic perturbations via untargeted metabolomics and redox profiling. RESULTS: OC, CA and MCA concentration-dependently reduced C. acnes adhesion (> 80%) without rapid bactericidal activity. Both CA and MCA covalently modified Cys359 of enolase (ENO), suppressing glycolytic flux and ATP generation. Independently, CA formed a thiohemiacetal adduct with coenzyme A (CoA), blocking acyl-transfer reactions required for fatty-acid metabolism and membrane biogenesis. The combined effects elevated the NADH/NAD+ ratio, disrupted oligosaccharide homeostasis, and impaired biofilm exopolysaccharide biosynthesis with altered monosaccharide composition, thereby compromising biofilm formation and driving C. acnes into a metabolically compromised state. CONCLUSION: OC-derived electrophiles act as metabolic modulators that incapacitate C. acnes adhesion and biofilm development through orthogonal inhibition of ENO and CoA-dependent pathways, providing a mechanistic blueprint for potential topical anti-acne therapies that circumvent conventional antibiotic resistance.