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Cutibacterium acnes metabolic and cell wall enzymes are a diverse group of proteins essential for the survival, structural integrity, and pathogenicity of the bacterium within the human skin environment [1, 3]. Cell wall enzymes, such as penicillin-binding proteins (PBPs) and Mur ligases, are responsible for the synthesis and maintenance of the peptidoglycan layer, which protects the bacterium from osmotic stress and is a primary target for beta-lactam antibiotics [1, 2]. Metabolic enzymes, including lipases (e.g., GehA), sialidases, and hyaluronidases, allow the bacterium to utilize sebum as a nutrient source and degrade host tissues, leading to the release of pro-inflammatory fatty acids and tissue damage [3, 4, 10]. Additionally, enzymes involved in fatty acid synthesis (e.g., KAS III) and DNA replication (e.g., DNA gyrase) are essential for bacterial proliferation and are targeted by quinolones and novel small-molecule inhibitors [5, 7, 8]. Targeting these enzymes is a cornerstone of acne therapy, aiming to reduce bacterial colonization and the subsequent inflammatory response while minimizing the impact on the beneficial skin microbiota [6, 9]. Recent research focuses on developing highly specific inhibitors and enzybiotics to overcome the rising challenge of antibiotic resistance [2, 8].
Inhibition of peptidoglycan synthesis by binding to penicillin-binding proteins, inhibition of DNA replication by targeting DNA gyrase and topoisomerase IV, inhibition of folic acid synthesis via dihydropteroate synthase, inhibition of fatty acid synthesis via KAS III, and direct enzymatic degradation of the cell wall peptidoglycan.
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