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

抗菌肽是生物体中宿主-寄生虫相互作用的重要效应分子。在脊椎动物中，它们通过对抗包括细菌、真菌和包膜病毒在内的各种微生物，发挥一线宿主防御的作用。抗生素活性被认为是基于它们的阳离子两亲性，这使得多肽能够损害重要的膜功能。这种活动的分子细节已经用模型膜(孔形成模型)进行了阐述，然而，越来越多的人担心，这些模型可能不能反映杀死微生物所涉及的复杂过程。通过对细菌多肽抗生素Nisin的研究，我们发现Nisin的整体杀伤活性是靶向介导的孔的形成、抑制细胞壁的生物合成、非靶向的孔的形成和诱导自溶等几个相互依赖和独立的活动的结果。我们建议研究那些在人类中发现的抗生素防御肽(α-和β-防御素、LL37和组他汀类)的分子作用模式，并调查它们是否主要形成孔，是否有特定的靶点参与膜穿孔，以及是否可能发现额外的抗生素活性。最终，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新一代抗生素的设计。

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.