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: 8961335
• 负责人: Jianfeng Cai
• 金额: $ 29.81万
• 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/8961335
• 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; Host Defense; Host Defense Mechanism; Immune response; Immune system; Infection; Inflammatory; Lead; Life; Light; Membrane; Methicillin Resistance; Modeling; Moderate Exercise; 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; public health relevance; 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21世纪人类面临的三大威胁之一。阳离子宿主防御肽（HDP）是小的阳离子两亲肽，是先天免疫系统的古老且重要的组成部分。 HDP 在防御细菌感染方面发挥着重要作用，因为它们对革兰氏阳性菌和革兰氏阴性菌均具有广谱活性。此外，由于细菌膜破坏的新机制，HDP 产生传统抗生素治疗耐药性的可能性较小。因此，HDP 因其抗菌功能而成为潜在的抗生素。然而，HDP 具有显着的缺点，例如易受酶促降解、低至中等活性及其不方便的优化。 我们最近开发了一类新的序列特异性肽模拟物，称为“a-AApeptides”。除了其固有的优势（包括增强的蛋白水解稳定性和化学修饰的无限潜力） 一些有效的分子表现出广谱抗菌活性，并且不会引起耐药病原体的明显耐药性。此外，它们还可以调节免疫反应并表现出强大的抗炎活性。此外，一种先导化合物在小鼠模型中显示出有效的体内抗 MRSA 活性。我们的初步数据表明，抗菌 a-AA 肽模仿 AMP 的整体结构、功能和机制。这些发现强烈表明 a-AA 肽可能是抗生素开发的新方法。我们的长期目标是开发一类新型抗菌肽模拟物（环脂化α-AA肽），具有治疗细菌感染性疾病的新机制。这里的目标是合成、开发和评估先前设计的抗菌环脂化 a-AA 肽的更有效的类似物。我们将首先设计和合成先前设计的抗菌环脂化α-AA肽的新型类似物。通过结构-功能-关系（SFR）研究，我们将鉴定出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，我们将评估它们的体内 在小鼠模型中的功效。 目标中提出的工作意义重大，因为它导致了新一类抗生素的鉴定，以对抗新出现的抗生素耐药性。这项工作具有创新性，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颖机制的一代抗生素。