Molecular Mode of Antibiotic Action of Defensins and Related Innate Immunity Peptides

防御素及相关先天免疫肽抗生素作用的分子模式

• 批准号: 5357590
• 负责人: Professor Dr. Hans-Georg Sahl
• 金额: --
• 依托单位: Arbeitsgruppe Pharmazeutische Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2006-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5357590?language=en
• 关键词: Molecular; Mode; Antibiotic; Action; Defensins

Antibiotic peptides are important effector molecules in host-parasite interactions throughout the living world. In vertebrates, they function in first line host defense by antagonizing a wide range of microbes including bacteria, fungi and enveloped viruses. The antibiotic activity is thought to be based on their cationic amphipathic nature which enables the peptides to impair vital membrane functions. Molecular details for such activities have been elaborated with model membranes (pore formation models), however, there is growing concern that these models may not reflect the complex processes involved in the killing of microbes. Having studied the bacterial peptide antibiotic nisin, we have found that the overall killing activity of nisin is the result of several interdependent and independent activities such as the formation of target-mediated pores, inhibition of cell wall biosynthesis, formation of non-targeted pores and induction of autolysis. We propose to study the molecular modes of action of those antibiotic defense peptides which are found in humans (alpha- and beta- defensins, LL37 and histatins) and to investigate whether they primarily form pores, whether specific targets are involved in membrane poration and whether additional antibiotic activities may be found. Ultimately, we want to increase our knowledge on how the most ancient tools of host defense and the most abundant antibiotics in nature function and eventually learn from this project for the design of new generations of antibiotics.

抗生素肽是整个生命世界中宿主与寄生虫相互作用的重要效应分子。在脊椎动物中，它们通过拮抗广泛的微生物（包括细菌、真菌和包膜病毒）在第一线宿主防御中发挥作用。抗生素活性被认为是基于它们的阳离子两亲性质，这使得肽能够损害重要的膜功能。这些活动的分子细节已经用模型膜（孔形成模型）进行了详细说明，然而，人们越来越担心这些模型可能无法反映杀死微生物的复杂过程。通过对细菌肽类抗生素Nisin的研究，我们发现Nisin的总体杀伤活性是由靶孔形成、细胞壁生物合成抑制、非靶孔形成和自溶诱导等几种相互依赖和独立的活性共同作用的结果。我们建议研究那些在人类中发现的抗生素防御肽的分子作用模式（α-和β-防御素，LL 37和组胺素），并研究它们是否主要形成孔，特定靶点是否参与膜穿孔以及是否可以发现额外的抗生素活性。我们希望增加我们对最古老的宿主防御工具和自然界中最丰富的抗生素如何发挥作用的知识，并最终从这个项目中学习，以设计新一代的抗生素。