Alpha-AApeptides as a novel class of antimicrobial biomaterials

 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(HDPs)是一种小的阳离子两亲性多肽，是天然免疫系统中一个古老而重要的组成部分。高密度脂蛋白在抵御细菌感染方面起着至关重要的作用，因为它们对革兰氏阳性和革兰氏阴性细菌都具有广谱活性。此外，由于细菌膜破坏的新机制，在常规抗生素治疗中观察到的HDPs可能不太可能产生耐药性。因此，高密度脂蛋白因其抗菌功能而成为潜在的抗生素。然而，HDPs具有明显的缺点，如对酶降解敏感，活性低到中等，优化不便。我们最近开发了一类新的序列特异性多肽模拟物，称为“α-AA肽”。除了它们的固有优势之外，包括增强了对蛋白质降解的稳定性和无限的化学修饰潜力， 一些有效的分子表现出广谱的抗菌活性，对耐药病原体不会诱导明显的耐药性。此外，它们还可以调节免疫反应，并显示出强大的抗炎活性。此外，一种先导化合物在小鼠模型中显示出强大的体内抗MRSA活性。我们的初步数据表明，抗菌α-AA肽模拟了AMPs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一种新途径。我们的长期目标是开发一类新的抗菌肽模拟物(环脂化α-A肽)，具有治疗细菌感染性疾病的新机制。本研究的目的是合成、开发和评价先前设计的更有效的抗菌环脂化α-A肽类似物。我们将首先设计和合成先前设计的抗菌环脂化α-A肽的新类似物。通过结构-功能-关系(SFR)研究，我们将确定具有强大和广谱活性的环状脂化铅a-A肽，以对抗一组临床相关的革兰氏阴性和革兰氏阳性细菌。然后，我们将调查细菌膜破坏是否是环状脂化a-A肽的一般杀菌机制。最后，我们将在体内评估它们的 在小鼠模型中的疗效。AIMS中提出的工作具有重要意义，因为它导致识别出对抗新出现的抗生素耐药性的新型抗生素。这项工作具有创新性，因为这些α-AA肽类似于HDPs的防御机制，并具有强大的广谱活性。它们是可修改的，用于开发具有新机制的一代抗生素。

 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.