University of Strasbourg, Biomatériaux et ingénierie Tissulaire, Inserm U977, Strasbourg, France.
Curr Med Chem. 2012;19(24):4115-23. doi: 10.2174/092986712802430063.
New endogenous antimicrobial peptides (AMPs) derived from chromogranin A (CgA) are secreted by nervous, endocrine and immune cells during stress. They display antimicrobial activities by lytic effects at micromolar range using a pore-forming mechanism against Gram-positive bacteria, filamentous fungi and yeasts. These AMPs can also penetrate quickly into neutrophils (without lytic effects), where, similarly to "cell penetrating peptides", they interact with cytoplasmic calmodulin, and induce calcium influx via Store Operated Channels therefore triggering neutrophils activation. Staphylococcus aureus and Salmonella enteritis are bacteria responsible for severe infections. We investigated here the effects of S. aureus and S. enteritis bacterial proteases on CgA-derived peptides and evaluated their antimicrobial activities. We showed that the Glu-C protease produced by S. aureus V8 induces the loss of the AMPs antibacterial activities and produces new antifungal peptides. In addition, four antimicrobial CGA-derived peptides (chromofungin, procatestatin, human/bovine catestatin) are degraded when treated with bacterial supernatants from S. aureus and S. enteritis, whereas, cateslytin, the short active form of catestatin, resists to this degradation. Finally, we demonstrate that several antimicrobial CgA-derived peptides are able to act synergistically with antibiotics against bacteria and fungi indicating their roles in innate defense.
新的内源性抗菌肽（AMPs）来源于嗜铬粒蛋白 A（CgA），在应激状态下由神经、内分泌和免疫细胞分泌。它们通过形成孔的机制在微摩尔范围内发挥溶菌作用，对革兰氏阳性菌、丝状真菌和酵母具有抗菌活性。这些 AMPs 还可以快速穿透中性粒细胞（无溶菌作用），在中性粒细胞中，类似于“细胞穿透肽”，它们与细胞质钙调蛋白相互作用，并通过储存操作通道诱导钙离子内流，从而触发中性粒细胞的激活。金黄色葡萄球菌和肠炎沙门氏菌是引起严重感染的细菌。我们在这里研究了金黄色葡萄球菌和肠炎沙门氏菌细菌蛋白酶对 CgA 衍生肽的作用，并评估了它们的抗菌活性。我们表明，金黄色葡萄球菌 V8 产生的 Glu-C 蛋白酶诱导 AMPs 抗菌活性丧失，并产生新的抗真菌肽。此外，当用金黄色葡萄球菌和肠炎沙门氏菌的细菌上清液处理时，四种抗菌 CGA 衍生肽（chromofungin、procatestatin、人/牛 catestatin）被降解，而 catestatin 的短活性形式 cateslytin 则抵抗这种降解。最后，我们证明几种抗菌 CgA 衍生肽能够与抗生素协同作用对抗细菌和真菌，表明它们在先天防御中的作用。
