Alpha-AApeptides as a novel class of antimicrobial biomaterials

α-AA肽作为一类新型抗菌生物材料

• 批准号: 9260896
• 负责人: Jianfeng Cai
• 金额: $ 29.54万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260896
• 关键词: Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Biochemical; Biocompatible Materials; Biological Assay; Biophysics; Cations; Chemicals; Combating Antibiotic Resistant Bacteria; Cytolysis; Data; Development; Drug resistance; Eukaryotic Cell; Evaluation; Foundations; Future; Generations; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Host Defense; Host Defense Mechanism; Immune response; Infection; Inflammatory; Innate Immune System; Lead; Life; Light; Literature; Membrane; Modeling; Moderate Activity; Modification; Mus; Organism; Outcome; Peptide Antibiotics; Peptides; Periodicity; Play; Predisposition; Probability; Property; Proteolysis; Public Health; Publishing; Pulmonary Surfactants; Research; Resistance; Role; Structure; Structure-Activity Relationship; Testing; Thigh structure; Toxic effect; Work; World Health Organization; agricultural pesticide; amphiphilicity; analog; antimicrobial; antimicrobial drug; bactericide; base; clinically relevant; combat; cytokine; design; experimental study; fighting; in vivo; innovation; killings; methicillin resistant Staphylococcus aureus; mimicry; mouse model; novel; novel strategies; pathogen; peptidomimetics; public health relevance; sound; virtual

 DESCRIPTION: Antibiotic resistance is currently one of the most significant public health concerns. The World Health Organization recently identified antimicrobial resistance as one of the three greatest threats facing mankind in the 21st century. Cationic host-defense peptides (HDPs) are small cationic amphiphilic peptides, and are an ancient and vital part of the innate immune system. HDPs play an essential role in the defense against bacterial infections, as they have broad-spectrum activity against both Gram-positive and Gram-negative bacteria. In addition, HDPs may have less probability to develop drug-resistance observed for conventional antibiotic treatment due to the novel mechanism of bacterial membrane disruption. As such, HDPs are potential antibiotics due to their antibacterial function. However, HDPs have significant drawbacks such as susceptibility to enzymatic degradation, low-to-moderate activity and their inconvenient optimization. We have recently developed a new class of sequence-specific peptidomimetics termed "a-AApeptides". In addition to their intrinsic advantages including enhanced stability against proteolysis and limitless potential for chemical modification, some potent molecules display broad-spectrum antimicrobial activity, and do not induce apparent resistance in drug-resistant pathogens. Furthermore, they can also modulate immune responses and show strong anti-inflammatory activity. In addition, one lead compound has shown potent in vivo activity against MRSA in mouse model. Our preliminary data suggest that antimicrobial a-AApeptides mimic the global structure, function and mechanism of AMPs. These findings strongly suggest a-AApeptides may be a new approach for antibiotic development. Our long-term goal is to develop a new class of antimicrobial peptidomimetics (cyclic-lipidated a-AApeptides) with novel mechanisms in the treatment of bacterial infectious disease. The objective here is to synthesize, develop and evaluation of more potent analogs of previously designed antimicrobial cyclic-lipidated a-AApeptides. We will first design and synthesize novel analogs of previously designed antimicrobial cyclic-lipidated a-AApeptides. Through structure-function-relationship (SFR) studies, we will identify lead cyclic-lipidated a-AApeptides that have potent and broad-spectrum activity against a panel of clinically- relevant Gram-negative and Gram-positive bacteria. We will then investigate if bacterial membrane disruption is the general bactericidal mechanism of lead cyclic-lipidated a-AApeptides. Finally, we will assess their in vivo efficacy in a mouse model. The work proposed in the aims is significant because it leads to the identification of new class of antibiotics combating emergent antibiotic resistance. The work is innovative because these a-AApeptides resemble the defense mechanisms of HDPs, and have potent broad-spectrum activity. They are amendable for development of a generation of antibiotics with novel mechanisms.

 描述：抗生素耐药性是目前最重要的公共卫生问题之一。世界卫生组织最近将抗菌素耐药性确定为人类在21世纪世纪面临的三大威胁之一。阳离子宿主防御肽（HDP）是一类小分子阳离子两亲性肽，是先天免疫系统中古老而重要的组成部分。HDP在防御细菌感染中起着重要作用，因为它们对革兰氏阳性菌和革兰氏阴性菌都具有广谱活性。此外，由于细菌膜破坏的新机制，HDPs可能不太可能产生常规抗生素治疗中观察到的耐药性。因此，由于其抗菌功能，HDPs是潜在的抗生素。然而，HDPs具有显著的缺点，例如对酶降解的敏感性、低至中等的活性以及它们不方便的优化。 我们最近开发了一类新的序列特异性肽模拟物，称为“a-AA肽”。除了其固有的优点，包括增强的抗蛋白水解的稳定性和化学修饰的无限潜力， 一些有效的分子显示出广谱抗微生物活性，并且在耐药病原体中不诱导明显的耐药性。此外，它们还可以调节免疫反应并显示出强烈的抗炎活性。此外，一种先导化合物在小鼠模型中显示出有效的抗MRSA的体内活性。我们的初步数据表明，抗微生物α-AA肽模拟AMP的整体结构、功能和机制。这些发现有力地表明α-AA肽可能是抗生素开发的新途径。我们的长期目标是开发一类具有治疗细菌感染性疾病的新机制的新型抗微生物肽模拟物（环状脂化α-AA肽）。本文的目的是合成、开发和评价先前设计的抗微生物环状脂化α-AA肽的更有效的类似物。我们将首先设计并合成先前设计的抗微生物环状脂化α-AA肽的新型类似物。通过结构-功能-关系（SFR）研究，我们将鉴定对一组临床相关的革兰氏阴性和革兰氏阳性细菌具有有效和广谱活性的先导环状脂化α-AA肽。然后，我们将研究细菌膜破坏是否是先导环脂化α-AA肽的一般杀菌机制。最后，我们将评估其在体内 在小鼠模型中的功效。 目标中提出的工作是重要的，因为它导致识别新的抗生素类别，以对抗紧急的抗生素耐药性。这项工作是创新的，因为这些a-AA肽类似于HDP的防御机制，并且具有有效的广谱活性。它们可用于开发具有新机制的一代抗生素。