Antimicrobial agents derived from AApeptide biomaterials

抗生素耐药性最近被确定为21世纪人类面临的三大威胁之一 世纪由世界卫生组织主办。对抗抗生素耐药性的一个有希望的方法是再投资- 获取已知的抗生素并设计它们的衍生品，希望找出新的抗生素制剂，使之符合人类的需求。 蝙蝠对抗生素的抗药性。海因是2，4-咪唑烷二酮的衍生物，已被开发用于抗肿瘤 长时间使用细菌。海因衍生物的作用机理复杂且不是很好。 了解，可能是由于它们对细菌DNA的破坏，以及细菌核糖体的结合和抑制 关键的细菌酵素。一种海因衍生物呋喃妥因被批准用于治疗尿路感染。 特兹。作为一种古老的抗生素，它最近引起了人们的极大兴趣，因为它们的细菌再感染几率很低。 与其他常规抗生素(如氟喹诺酮类)相比的耐药性，可能是由于它们的混合 作用机制。然而，包括呋喃妥因在内的海因衍生物通常只表现出中等程度的 抗菌活性，这限制了它们在对抗新出现的抗生素耐药性方面的进一步应用。 在过去的RO1阶段，我们开发了一系列新型的抗菌肽。通过适当的脱脂 标记和修饰，我们最近开发了一系列新型的膜活性海因衍生物 来源于显示出强大和广谱抗菌活性的多肽(25-100倍的硝基- 在体外和体内)。我们的初步研究强烈表明，这些化合物是一种新的治疗方法 抗生素的发展。因此，我们的长期目标是开发具有新机制的新型抗菌剂- 对抗耐药细菌感染的NIMS。这里的目标是进一步开发这些海因 通过优化现有的先导化合物，使其具有更大的效力。我们的中心假设是 这些药剂经过适当的设计和修饰，可以通过新颖的方法进一步提高杀菌效果。 机械装置。为了测试我们的中心假设，从而实现此应用程序的目标，我们将 首先设计和合成以前开发的铅分子的类似物，并确定更有效的摩尔- 对两种革兰氏阳性耐甲氧西林金黄色葡萄球菌(MIC≤)都有活性的CRU 最低抑菌浓度(≤)为1微克/毫升。接下来，我们将研究是否具有杀菌作用 先导化合物的作用机制涉及膜作用，并评估其诱导抗生素重新产生的可能性。 抵抗。此外，我们将评估先导化合物在大腿感染小鼠模型中的体内活性， 以展示其作为具有新机制的新一代抗生素的潜力。 提出的工作是创新的，因为这些化合物是一类新的海因化合物， 用新的机制杀死革兰氏阳性和革兰氏阴性细菌。它们是高度可修改的 衍生化和最优化，并具有较低的诱导抗生素耐药性的倾向。拟议中的工作 这一点意义重大，因为目前还没有有效的方法来对抗新出现的耐药性。我们的再- 搜索策略将导致一种有前景的治疗方法来治疗抗生素耐药病原体。

Antibiotic resistance has recently been identified as one of the three greatest threats facing mankind in the 21st century by World Health Organization. One promising approach to combat antibiotic resistance is to reinvesti- gate known antibiotics and design their derivatives, in the hope of identifying novel antibiotic agents that com- bat antibiotic resistance. Hydantoins, the derivatives of 2,4-imidazolidinedione, have been developed for anti- bacterial applications for long time. The mechanism of action for hydantoin derivatives is complex and not well understood, possibly due to their damage to bacterial DNA, as well as bacterial ribosome binding and inhibition of critical bacterial enzymes. One hydantoin derivative, nitrofurantoin, was approved to treat urinary tract infec- tions. As an old antibiotic, it recently attracted considerable interest due to their low probability of bacterial re- sistance compared to other conventional antibiotics such as fluoroquinolones, possibly owing to their mixed mechanism of action. However, hydantoin derivatives including nitrofurantoin generally exhibit only moderate antibacterial activity, which limits their further application in combating emergent antibiotic resistance. In the last RO1 period, we have developed a series of novel antimicrobial AApeptides. Through proper de- sign and modification, we have recently developed a series of novel membrane-active hydantoin derivatives derived from AApeptides that display potent and broad-spectrum antimicrobial activity (25-100 fold of nitrofu- rantoin) in vitro and in vivo. Our preliminary studies strongly suggest these compounds as a new approach for antibiotic development. As such, our long-term goal is to develop novel antibiotic agents with novel mecha- nisms to combat drug-resistant bacterial infections. The objective here, is to further develop these hydantoin derivatives with greater potency through optimization of current lead compounds. Our central hypothesis is that these agents, with proper design and modification, could be further improved in bacterial killing through novel mechanisms. To test our central hypothesis and, thereby, accomplish the objective of this application, we will first design and synthesize analogs of previously developed lead molecules, and identify more potent mole- cules that are active against both Gram-positive Methicillin-resistant Staphylococcus aureus (MRSA) (MIC ≤ 0.5 µg/ml) and Gram-negative Pseudomonas aeruginosa (MIC ≤ 1 µg/mL). Next, we will study if bactericidal mechanism of lead compounds involves membrane action, and assess their probability to elicit antibiotic re- sistance. Furthermore, we will evaluate the in vivo activity of lead compounds in a thigh-infection mouse model, in order to demonstrate their potential as a new generation of antibiotics with novel mechanisms. The work proposed is innovative because these compounds are a new class of hydantoin compounds that kill both Gram-positive and Gram-negative bacteria with novel mechanisms. They are highly amendable for derivatization and optimization, and possess low propensity to induce antibiotic resistance. The proposed work is significant because currently there are no effective methods to combat emerging drug resistance. Our re- search strategy will lead to a promising therapeutic approach to treat antibiotic resistant pathogens.