McInturff Jamie E, Wang Shyh-Jeun, Machleidt Thomas, Lin T Richard, Oren Ami, Hertz Cheryl J, Krutzik Stephan R, Hart Scott, Zeh Karin, Anderson Daniel H, Gallo Richard L, Modlin Robert L, Kim Jenny
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
J Invest Dermatol. 2005 Aug;125(2):256-63. doi: 10.1111/j.0022-202X.2005.23805.x.
Propionibacterium acnes is a key therapeutic target in acne, yet this bacterium has become resistant to standard antibiotic agents. We investigated whether the human antimicrobial protein granulysin is a potential candidate for the treatment of acne. Granulysin and synthetic granulysin-derived peptides possessing a helix-loop-helix motif killed P. acnes in vitro. Modification of a helix-loop-helix peptide, 31-50, by substitution of a tryptophan for the valine at amino acid 44 (peptide 31-50v44w) to increase its interaction with bacterial surfaces also increased its antimicrobial activity. Moreover, when synthesized with D- rather than L-type amino acids, this peptide (D-31-50v44w) became less susceptible to degradation by proteases and more effective in killing P. acnes. Granulysin peptides were bactericidal, demonstrating an advantage over standard bacteriostatic antibiotics in their control of P. acnes. Moreover, peptide D-31-50v44w killed P. acnes in isolated human microcomedone preparations. Importantly, peptides 31-50, 31-50v44w, and D-31-50v44w also have potential anti-inflammatory effects, as demonstrated by suppression of P. acnes-stimulated cytokine release. Taken together, these data suggest that granulysin peptides may be useful as topical therapeutic agents, providing alternatives to current acne therapies.
痤疮丙酸杆菌是痤疮治疗的关键靶点，但这种细菌已对标准抗生素产生耐药性。我们研究了人类抗菌蛋白颗粒溶素是否是治疗痤疮的潜在候选物。颗粒溶素和具有螺旋-环-螺旋基序的合成颗粒溶素衍生肽在体外可杀死痤疮丙酸杆菌。通过将44位氨基酸的缬氨酸替换为色氨酸对螺旋-环-螺旋肽31-50进行修饰（肽31-50v44w），以增加其与细菌表面的相互作用，也增强了其抗菌活性。此外，当用D型而非L型氨基酸合成时，该肽（D-31-50v44w）对蛋白酶降解的敏感性降低，对痤疮丙酸杆菌的杀伤更有效。颗粒溶素肽具有杀菌作用，在控制痤疮丙酸杆菌方面显示出优于标准抑菌抗生素的优势。此外，肽D-31-50v44w在分离的人类微粉刺制剂中可杀死痤疮丙酸杆菌。重要的是，肽31-50、31-50v44w和D-31-50v44w也具有潜在的抗炎作用，这已通过抑制痤疮丙酸杆菌刺激的细胞因子释放得到证实。综上所述，这些数据表明颗粒溶素肽可能作为局部治疗药物有用，为目前的痤疮治疗提供替代方案。
