Whole Genome Sequencing Reveals Antibiotic Resistance Heterogeneity and Metabolic Signatures of Cutibacterium acnes in Atopic Dermatitis.

Cutibacterium acnes (C. acnes), the most abundant microbe of the skin microbiota, has been reported playing a protective role in atopic dermatitis (AD), in contrast to its proinflammatory role in acne. While antibiotic resistance in C. acnes has been extensively studied in acne, little is known about its characteristics in AD. Here, we performed an integrated genomic and functional analysis of 405 AD-derived C. acnes isolates using whole genome sequencing (WGS) and antimicrobial susceptibility testing. The result showed that antibiotic resistance genes (ARGs) were highly clustered within specific individuals and phylogenetic subtypes of C. acnes, with erm(X) being the most prevalent determinant conferring cross-resistance to erythromycin and clindamycin. To verify the high genotype-phenotype concordance (95.45%) of erythromycin and clindamycin resistance of 110 ARGs-carried C. acnes isolates, minimum inhibitory concentration (MIC) was performed. AD isolates exhibited low-level acquired resistance to tetracyclines, chloramphenicol, and fusidic acid, indicating distinct antibiotic exposure pressures in AD patients. Comparative genomic analysis and genome-wide association study both showed that metabolism and quorum sensing related pathways were enriched in pan-genome of ARG-containing strains. These findings suggest that resistance in AD-associated C. acnes is linked to metabolic adaptations that may facilitate survival in the AD skin environment. Together, these findings provide a genomic and functional framework for understanding the antibiotic resistance of AD-associated C. acnes, underscoring the need for careful antibiotic stewardship in AD management.