Spin-Labeled Peptide Antibiotics

自旋标记肽抗生素

• 批准号: 7650622
• 负责人: Jimmy Feix
• 金额: $ 32.81万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650622
• 关键词: Affinity; Amino Acids; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antifungal Agents; Antiviral Agents; Bacterial Infections; Bee Venoms; Binding; Cell Wall; Cell membrane; Cells; Clinical; Communicable Diseases; Comparative Study; Development; Drug Delivery Systems; Drug resistance; Drug-sensitive; Effectiveness; Electron Spin Resonance Spectroscopy; Eukaryotic Cell; Funding; Generations; Goals; Gram-Negative Bacteria; Healthcare; Host Defense; Hybrids; Immersion Investigative Technique; Incidence; Infection; Insecta; Invertebrates; Knowledge; Lead; Lysine; Measures; Mediating; Membrane; Modification; Molecular; Multi-Drug Resistance; Natural Immunity; Outcome; Parents; Peptide Antibiotics; Peptides; Pharmaceutical Preparations; Physiologic pulse; Play; Polymers; Prevalence; Process; Property; Research; Resistance; Ribosomes; Role; Site; Specificity; Spin Labels; Structure; Toxic effect; Treatment Cost; Treatment Failure; United States; Upper arm; Vertebrates; analog; antimicrobial; antimicrobial peptide; base; cecropin; cecropin A; cytotoxic; design; drug resistant bacteria; improved; infectious disease treatment; insight; killings; meetings; membrane model; mortality; novel; novel strategies; pathogen; peptidomimetics; public health relevance; response

DESCRIPTION (provided by applicant): Infectious disease remains a leading cause of mortality worldwide. A significant aspect of this problem is the continuing rise of infections that are resistant to most, if not all, conventional antibiotics. To meet this challenge it is essential that new drug targets be identified, and new classes of antibiotics developed. Over the past two decades a large number of naturally-occurring antimicrobial peptides have been found in both vertebrate and invertebrate species that are capable of providing a rapid and broad-spectrum response against a wide variety of pathogens. Because the specificity of these peptides is based on recognition of general properties of the cell membrane the emergence of resistance is exceedingly rare, making them ideal starting points for the development of new antibiotics. One limiting factor in our ability to further enhance the efficacy of these peptides is a lack of detailed knowledge about the manner in which they interact with and disrupt target cell membranes. The studies outlined in this proposal are directed towards developing a clear understanding of peptide-membrane interactions for a promising class of antimicrobial peptides that are synthetic hybrids of the insect peptide cecropin A and the bee-venom peptide, mellitin. Site-directed spin labeling (SDSL) electron paramagnetic resonance (EPR) spectroscopy provides a powerful and well-established approach for the analysis of peptide-membrane interactions that is uniquely suited to providing such a detailed understanding. Specifically, we will use both conventional and pulsed SDSL EPR to measure membrane binding affinities, determine structure, topology, and degree of membrane insertion for cecropin-mellitin hybrid peptides in model membranes that mimic both eukaryotic and bacterial membranes. These properties will be related to antibiotic efficacy against a panel of drug-sensitive and drug-resistant bacteria. We will systematically modify peptide composition to define relationships between sequence, membrane interactions, and antibacterial efficacy. Finally, we will synthesize and evaluate the antibiotic efficacy and membrane interactions of peptidomimetic analogs composed of non-natural 2-amino acids. These studies will significantly advance our understanding of the mechanism of action of antimicrobial peptides, and contribute to the further development of peptide and peptidomimetic antibiotics. PUBLIC HEALTH RELEVANCE: The prevalence of multi-drug resistant (MDR) infections is one of the most serious problems in health care today, both in the United States and worldwide, leading to increased treatment costs and a growing incidence of treatment failure. There is a critical need for the development of new antibiotics, and in particular for new classes of compounds that target non-traditional sites other than cell-wall synthesis and the bacterial ribosome. Antimicrobial peptides, which display remarkable efficacy against a broad spectrum of pathogens, including those resistant to conventional antibiotics, offer a novel approach to the treatment of drug-resistant infections. Developing a more complete understanding of the interactions of antimicrobial peptides with their target cells will enhance our ability to design and develop more effective peptide and peptidomimetic antibiotics.

描述（由申请人提供）：传染病仍然是全世界死亡的主要原因。这个问题的一个重要方面是对大多数（如果不是全部）传统抗生素具有耐药性的感染持续增加。为了应对这一挑战，必须确定新的药物靶点并开发新类别的抗生素。在过去的二十年中，在脊椎动物和无脊椎动物物种中发现了大量天然存在的抗菌肽，它们能够对多种病原体产生快速和广谱的反应。由于这些肽的特异性是基于对细胞膜一般特性的认识，因此耐药性的出现极其罕见，这使得它们成为开发新抗生素的理想起点。我们进一步增强这些肽功效的能力的一个限制因素是缺乏关于它们与靶细胞膜相互作用和破坏靶细胞膜的方式的详细知识。该提案中概述的研究旨在对一类有前景的抗菌肽的肽-膜相互作用有一个清晰的认识，这些抗菌肽是昆虫肽天蚕素 A 和蜂毒肽蜂毒肽的合成混合物。定点自旋标记 (SDSL) 电子顺磁共振 (EPR) 光谱为分析肽-膜相互作用提供了一种强大且完善的方法，特别适合提供如此详细的理解。具体来说，我们将使用传统和脉冲 SDSL EPR 来测量膜结合亲和力，确定模拟真核和细菌膜的模型膜中天蚕素-蜂毒肽混合肽的结构、拓扑和膜插入程度。这些特性将与抗生素针对一组药物敏感和耐药细菌的功效相关。我们将系统地修改肽组成，以确定序列、膜相互作用和抗菌功效之间的关系。最后，我们将合成并评估由非天然2-氨基酸组成的拟肽类似物的抗生素功效和膜相互作用。这些研究将显着增进我们对抗菌肽作用机制的理解，并有助于肽和拟肽抗生素的进一步开发。公共卫生相关性：多重耐药性 (MDR) 感染的流行是当今美国和世界范围内医疗保健中最严重的问题之一，导致治疗成本增加和治疗失败发生率增加。迫切需要开发新的抗生素，特别是针对细胞壁合成和细菌核糖体以外的非传统位点的新型化合物。抗菌肽对多种病原体（包括对传统抗生素耐药的病原体）表现出显着的功效，为治疗耐药感染提供了一种新方法。更全面地了解抗菌肽与其靶细胞的相互作用将增强我们设计和开发更有效的肽和拟肽抗生素的能力。