Molecular Basis of Human Defensins as Novel Lipid II Binding Peptide Antibiotics

描述（由申请人提供）：耐药细菌病原体的流行使目前的抗生素无效，因此必须开发新药来对抗感染。防御素是一种具有抗细菌和病毒感染作用的抗菌肽，具有广泛的抗感染活性。该提案首次将细菌膜生物合成中的重要前体脂质II确定为防御素抗菌活性的潜在靶点。我们研究的总体目标是确定防御素和脂质II之间的功能和结构相互作用。从长远来看，我们的目标是将我们研究中获得的知识应用于开发基于防御素的抗生素化合物，以脂质II为靶点，以对抗革兰氏阳性病原体感染。 公共卫生相关性：抗生素耐药性感染的频率不断上升，这凸显了开发新型抗生素的迫切需要。该项目首次描述了防御素（人体中天然存在的抗菌化合物）与脂质II（细菌膜形成所必需的）之间的相互作用。我们的研究为防御素如何杀死细菌提供了新的线索，并且是将这些天然肽开发为新型，有效的抗生素制剂以对抗感染的重要第一步。

DESCRIPTION (provided by applicant): The prevalence of resistant bacterial pathogens is rendering current antibiotics ineffective, and making it essential that new drugs be developed to fight infection. Defensins are antimicrobial peptides that protect man against bacterial and viral infections and have a wide range as potential anti-infective therapeutics. This proposal identifies Lipid II, an essential precursor in bacterial membrane biogenesis, as a potential target of defensin antibacterial activity for the first time. The overall objective of our study is to define functional and structural interactions between defensins and Lipid II. In the long term, we aim to apply the knowledge gained in our research towards the development of defensin-based antibiotic compounds targeting Lipid II to combat Gram-positive pathogenic infections. PUBLIC HEALTH RELEVANCE: The escalating frequency of antibiotic resistant infections combined underscores the critical need to develop novel antibiotics. This project describes for the first time the interaction between defensins, naturally occurring antimicrobial compounds in humans and Lipid II, essential in the formation of bacterial membranes. Our research sheds new light on how defensins kill bacteria and is an important first step towards the development of these natural peptides as novel, effective antibiotic agents to combat infections.