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: 9095371
• 负责人: Jianfeng Cai
• 金额: $ 29.68万
• 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/9095371
• 关键词: Agriculture; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Biochemical; Biocompatible Materials; Biological Assay; Chemicals; Cyclic Peptides; Cytolysis; Data; Development; Drug resistance; Eukaryotic Cell; Evaluation; Foundations; Future; Generations; Genus staphylococcus; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Health; Host Defense; Host Defense Mechanism; Immune response; Immune system; Infection; Inflammatory; Lead; Life; Light; Membrane; Methicillin Resistance; Modeling; Moderate Activity; Modification; Mus; Outcome; Peptide Antibiotics; Peptides; Pesticides; 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; analog; antimicrobial; antimicrobial drug; bactericide; base; clinically relevant; combat; cytokine; design; fighting; in vivo; innovation; killings; mimicry; mouse model; novel; novel strategies; pathogen; peptidomimetics; research study; sound

 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：抗生素耐药性目前是最重要的公共卫生问题之一。世界卫生组织最近将抗菌素抗性确定为21世纪人类面临的三个最大威胁之一。阳离子宿主防御辣椒（HDPS）是小阳离子的两亲性胡椒粉，是先天免疫系统的古老而重要的部分。 HDP在防御细菌感染中起着至关重要的作用，因为它们具有针对革兰氏阳性和革兰氏阴性细菌的广谱活性。此外，由于细菌膜破坏的新机制，HDP可能较少发生用于常规抗生素治疗的药物抗性的可能性。因此，由于其抗菌功能，HDP是潜在的抗生素。但是，HDP具有明显的缺点，例如酶促降解的易感性，低到中度活性及其不便优化。我们最近开发了一种称为“ A-肽肽”的新型序列特异性肽仪。除了它们的内在优势，包括对蛋白水解的稳定性增强以及化学修饰的无限潜力， 一些锅分子表现出广泛的抗菌活性，并且不会引起抗药性病原体的明显耐药性。此外，它们还可以调节免疫复杂并显示出强大的抗炎活性。此外，一种铅化合物在小鼠模型中显示了针对MRSA的体内活性。我们的初步数据表明，抗微生物A-酰肽模仿AMP的整体结构，功能和机制。这些发现强烈表明A-磷酸可能是抗生素发育的一种新方法。我们的长期目标是开发一种新的抗菌肽肽（环状A-磷酸肽），并在治疗细菌传染病方面具有新颖的机制。这里的目的是合成，开发和评估先前设计的抗微生物循环蛋白A-肽的更多潜在类似物。我们将首先设计并合成先前设计的抗微生物循环蛋白A-肽的新型类似物。通过结构功能关系（SFR）研究，我们将确定具有潜在和广谱活性与一组临床上相关的革兰氏阴性和革兰氏阴性细菌的潜在和广谱活性的铅环状A-肽。然后，我们将研究细菌膜的破坏是否是铅环蛋白A-洗肽的一般杀菌机制。最后，我们将评估他们的体内 鼠标模型的功效。目的中提出的工作非常重要，因为它导致鉴定出新的抗生素抗生素抗生素耐药性。这项工作具有创新性，因为这些A-肽类似于HDP的防御机制，并且具有潜在的广谱活动。它们是为开发具有新颖机制的一代抗生素的修正案。