Biological Evaluation of the Antibacterial Retinoid CD437 in Cutibacterium acnes Infection

作者：Huang, Xiao-wen; Pan, Wen; Zhong, Mei-zhen; Chhonker, Yashpal Singh; Steele, Andrew D.; Keohane, Colleen E.; Mishra, Biswajit; Lucas, Lewis Oscar Felix Raj; Murry, Daryl J.; Ausubel, Frederick M.; Wuest, William M.; Li, Chang-xing^*; Mylonakis, Eleftherios^*

来源：Antimicrobial Agents and Chemotherapy, 2023, 67(4).

DOI：10.1128/aac.01679-22

• CD437
• acne
• inflammation
• irritation

Acne vulgaris is a complex skin disease involving infection by Cutibacterium acnes, inflammation, and hyperkeratinization. We evaluated the activity of the retinoid 6-[3-(adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and 16 other retinoid analogs as potential anti-C. acnes compounds and found that CD437 displayed the highest antimicrobial activity with an MIC against C. acnes (ATCC 6919 and HM-513) of 1 mu g/mL. CD437 demonstrated an MBC of 2 mu g/mL compared to up to 64 mu g/mL for the retinoid adapalene and up to 16 mu g/mL for tetracycline, which are commonly used clinically to treat acne. Membrane permeability assays demonstrated that exposure of C. acnes ATCC 6919 to CD437 damaged the integrity of C. acnes ATCC 6919 bacterial membranes, and this finding was confirmed with scanning electron microscopy. Additionally, CD437 downregulated the expression of C. acnes ATCC 6919 virulence factors, including the genes encoding Christie-Atkins-Munch-Petersen factor 1 (CAMP1), CAMP2, glycerol-ester hydrolase B (GehB), sialidase B, and neuraminidase. In a mouse skin infection model of C. acnes ATCC 6919, topical treatment with CD437 ameliorated skin lesions and reduced the bacterial burden in situ (P < 0.001). In human NHEK primary cells, CD437 reduced the transcriptional levels of the coding genes for inflammatory cytokines (interleukin-1 alpha, similar to 10-fold; interleukin-6, similar to 20-fold; interleukin-8, similar to 30-fold; and tumor necrosis factor-alpha, similar to 6-fold) and downregulated the transcriptional levels of KRT10 (similar to 10-fold), FLG (similar to 4-fold), and TGM1 (similar to 2-fold), indicating that CD437 can diminish inflammation and hyperkeratinization. In summary, CD437 deserves further attention for its dual function as a potential acne therapeutic that potentially acts on both the pathogen and the host.

• 单位
  南方医科大学