The Impact of Bacterial Fatty Acid Structure on the Activity of Antimicrobial Pep

描述(申请人提供)：这个项目的目标是双重的。首先，我们试图研究细菌脂类中典型的酰基链结构对抗菌肽活性的影响。其次，我们将确定具有特定脂质结构的抗菌肽的酰化是否会在保持高治疗指数的同时产生更有效的抗菌剂。到目前为止，大多数关于抗菌肽与模型双层系统相互作用的研究都集中在容易获得的脂类上，这些脂类只存在于许多细菌的细胞膜上，数量可以忽略不计，或者根本不存在，这些脂类对人类的健康构成了威胁。我们认为，这种方法过度简化了复杂的细菌细胞膜，细菌脂的酰基链结构在细菌对抗菌肽的敏感性中起着至关重要的作用。我们将通过在模型系统中使用天然和合成来源的细菌脂，以及在细菌培养中研究多肽-膜相互作用来检验这一假设。我们进一步建议，抗菌肽的有效性可以通过添加脂锚来增强，根据其结构，脂锚有助于多肽诱导的膜扰动。了解各种细菌中发现的脂质的重要性将有助于我们克服细菌对当前抗生素的适应，并设计如何有效地对抗病原菌的新策略。1 与公共卫生相关：细菌对常规抗生素的耐药性正在上升。在包括人类在内的大多数生物中，抗菌肽通常是抵御入侵微生物的第一道防线。本项目旨在研究独特的细菌脂结构在细菌对抗菌肽敏感性中的作用，并开发新的抗生素设计策略。

DESCRIPTION (provided by applicant): The goal of this project is twofold. First, we seek to study the impact of acyl chain structures typically found in bacterial lipids on antimicrobial peptide activity. Second, we will determine if acylation of an antimicrobial peptide with specific lipid structures will yield a more efficient antimicrobial agent while maintaining a high therapeutic index. To this date, most studies on the interaction of antimicrobial peptides with model bilayer systems have focused on readily available lipids that exist in only negligible quantities or not at all in cell membranes of many bacteria that represent a health threat to humans. We suggest that this approach has oversimplified the complex bacterial cell membrane and that the acyl chain structure of bacterial lipids plays a crucial role in the sensitivity of bacteria to antimicrobial peptides. We will test this hypothesis by studying peptide-membrane interactions in model systems using bacterial lipids of both natural and synthetic origin, and in bacterial cultures. We further suggest that the efficacy of antimicrobial peptides can be enhanced by the addition of a lipid anchor that, depending on its structure, facilitates peptide-induced membrane perturbation. Understanding the significance of lipids found in a variety of bacteria will help us to overcome bacterial adaptations to current antibiotics and to design new strategies of how to efficiently combat pathogenic bacteria. 1 PUBLIC HEALTH RELEVANCE: Bacterial resistance to conventional antibiotics is on the rise. Antimicrobial peptides are usually the first line of defense against invading microorganisms in most organisms, including humans. This project seeks to study the role of unique bacterial lipid structures in bacterial sensitivity to antimicrobial peptides and to develop new design strategies for novel antibiotics.