Antimicrobial agents derived from AApeptide biomaterials

源自AA肽生物材料的抗菌剂

• 批准号: 10396434
• 负责人: Jianfeng Cai
• 金额: $ 37.38万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396434
• 关键词: Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial DNA; Bacterial Infections; Binding; Biochemical; Biocompatible Materials; Biophysics; Combating Antibiotic Resistant Bacteria; Complex; Data; Development; Drug resistance; Enzymes; Exhibits; Fluorescence Microscopy; Fluoroquinolones; Foundations; Generations; Goals; Gram-Negative Bacteria; Host Defense Mechanism; Hydantoins; In Vitro; Infection; Lead; Life; Light; Literature; Membrane; Methods; Modeling; Modification; Molecular; Multi-Drug Resistance; Mus; National Institute of General Medical Sciences; Nitrofurantoin; Outcome; Peptides; Probability; Pseudomonas aeruginosa; Publishing; Research; Resistance; Ribosomes; Series; Testing; Therapeutic; Thigh structure; Time; Toxic effect; Urinary tract infection; Work; World Health Organization; analog; antibiotic design; antimicrobial; antimicrobial drug; bacterial resistance; bactericide; base; clinically relevant; combat; design; drug resistant pathogen; experimental study; improved; in vivo; innovation; interest; methicillin resistant Staphylococcus aureus; mouse model; novel; novel antibiotic class; novel strategies; pathogenic bacteria; small molecule; sound

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.

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 世界卫生组织提出的一个有希望的对抗抗生素耐药性的方法是重新研究。 筛选已知的抗生素并设计它们的衍生物，希望能够识别出包含以下成分的新型抗生素药物： 乙内酰脲（2,4-咪唑烷二酮的衍生物）已被开发用于抗抗生素耐药性。 乙内酰脲衍生物的作用机制复杂且效果不佳。 理解，可能是由于它们对细菌 DNA 的损害，以及细菌核糖体的结合和抑制 一种乙内酰脲衍生物，呋喃妥因，被批准用于治疗尿路感染。 作为一种古老的抗生素，由于其细菌繁殖的可能性较低，最近引起了人们的广泛关注。 与其他传统抗生素（例如氟喹诺酮类）相比，其耐药性可能是由于它们的混合 然而，包括呋喃妥因在内的乙内酰脲衍生物通常仅表现出中等程度的作用。 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时期，我们通过适当的研究开发了一系列新型抗菌A肽。 经过标记和修饰，我们最近开发了一系列新型膜活性乙内酰脲衍生物 源自具有强效广谱抗菌活性的 A 肽（硝基呋喃的 25-100 倍） rantoin）在体外和体内的初步研究强烈表明这些化合物是一种新的方法。 因此，我们的长期目标是开发具有新机制的新型抗生素药物。 我们的目标是进一步开发这些乙内酰脲。 通过优化当前先导化合物，获得更强大的衍生物。我们的中心假设是： 这些药剂经过适当的设计和修改，可以通过新颖的方法进一步提高细菌杀灭能力。 为了检验我们的中心假设，从而实现本应用程序的目标，我们将 首先设计并合成先前开发的先导分子的类似物，并确定更有效的分子 对革兰氏阳性耐甲氧西林金黄色葡萄球菌 (MRSA) 均具有活性的微生物 (MIC ≤ 0.5 µg/ml) 和革兰氏阴性铜绿假单胞菌 (MIC ≤ 1 µg/mL) 接下来，我们将研究是否具有杀菌作用。 先导化合物的机制涉及膜作用，并评估它们引起抗生素再反应的可能性 此外，我们将评估大腿感染小鼠模型中化合物中铅的体内活性， 以证明它们作为具有新颖机制的新一代抗生素的潜力。 所提出的工作具有创新性，因为这些化合物是一类新型乙内酰脲化合物， 它们以新颖的机制同时杀死革兰氏阳性和革兰氏阴性细菌。 衍生化和优化，并且具有较低的诱导抗生素耐药性的倾向。 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。 搜索策略将带来一种有前途的治疗方法来治疗抗生素耐药性病原体。