Development of Novel Antimicrobial Peptide Mimics

新型抗菌肽模拟物的开发

• 批准号: 7928810
• 负责人: PAUL B SAVAGE
• 金额: $ 67.35万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-09 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928810
• 关键词: Anti-Bacterial Agents; Antimicrobial Resistance; Bacteria; Biological Assay; Bioterrorism; Blood Circulation; Brain; Categories; Child; Classification; Clinical; Clostridium difficile; Development; Dose; Drug Formulations; Drug resistance; Early identification; Escherichia coli; Food; Gastrointestinal tract structure; Goals; Growth; Health; Human; Infection; Infection prevention; Insecta; Instruction; Intestines; Lead; Length of Stay; Listeria monocytogenes; Logistics; Measures; Membrane; Methods; Microbe; Minor; Modification; Natural Immunity; Oral; Oral Administration; Organism; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Play; Production; Recovery; Research; Research Personnel; Resistance; Risk; Role; Salmonella; Series; Shigella; Structure; Time; Tissues; Toxic effect; Variant; Vesicle; Vibrio; Water Pollution; Water Supply; Yersinia enterocolitica; absorption; antimicrobial; antimicrobial drug; antimicrobial peptide; base; cathelicidin; cecropin; falls; foodborne; in vivo; killings; magainin; manufacturing process development; mortality; novel; pathogen; pathogenic bacteria; prevent; programs; research and development; research study; small molecule; waterborne

DESCRIPTION (provided by applicant): Ceragenins are small molecule mimics of endogenous antimicrobial peptides. They are broad-spectrum antimicrobial agents with activity against common and drug-resistant pathogens. Antimicrobial peptides play a central role in controlling bacterial growth in multiple tissues, including in the gastrointestinal tract. Antimicrobial peptides have been found in organisms ranging from humans to insects, and their ubiquity argues that they have evolved independently numerous times. This observation argues that the mechanism by which they eliminate bacteria provides a sustainable means of controlling bacterial growth. However, antimicrobial peptides are relatively difficult to prepare on a large scale and in general they are substrates for proteases. The ceragenins are relatively simple to prepare, and because they are not based on peptides, they are not substrates for proteases. In multiple direct comparisons of ceragenins and selected antimicrobial peptides, their mechanisms of action are indistinguishable. Intestinal infections kill millions of people annually, hinder the development of tens of millions of children, prolong hospital stays, increase mortality of hospitalized patients, and have become a concern as potential means of bioterrorism by contamination of water and food. The emergence of drug-resistant pathogens causing intestinal infections has added to this concern and has contributed to the call for new antimicrobials that will not engender resistance. The ceragenins are active against intestinal pathogens and are well- tolerated orally. Steps toward clinical use of the ceragenins include large-scale synthesis, formulation, toxicity and effacy studies. These steps are proposed. In addition, specific ceragenins display very high levels of activity against certain clinical isolates of Clostridium difficile, and it is expected that minor modifications to ceragenins will result in compound with broad, selective activity against this human pathogen. Studies of the interactions with membranes from C. difficile and a modest structure-activity study are proposed to better target ceragenins to C. difficile. RELEVANCE (See instructions): Targeted organisms are Shigella spp. and C. difficile (including drug-resistant forms). The ceragenins are also active against the following organisms: E. coli, Vibrios, Salmonella, Listeria monocytogenes, Campylobacteria jejuni and Yersinia enterocolitica (all Category B Pathogens). The research and development of the ceragenins falls within the field of "innate immunity" which is also listed in Class C.

描述（由申请人提供）：Ceragenins 是内源性抗菌肽的小分子模拟物。它们是广谱抗菌剂，对常见和耐药病原体具有活性。抗菌肽在控制多种组织（包括胃肠道）细菌生长方面发挥着核心作用。从人类到昆虫的各种生物体中都发现了抗菌肽，它们的普遍存在表明它们已经独立进化了无数次。这一观察结果表明，它们消除细菌的机制提供了控制细菌生长的可持续方法。然而，抗菌肽相对难以大规模制备，并且通常它们是蛋白酶的底物。角藻蛋白的制备相对简单，并且由于它们不是基于肽，因此它们不是蛋白酶的底物。在对角藻素和选定抗菌肽的多次直接比较中，它们的作用机制是无法区分的。肠道感染每年导致数百万人死亡，阻碍数以千万计儿童的发育，延长住院时间，增加住院患者的死亡率，并且由于水和食品污染而成为生物恐怖主义的潜在手段，已成为令人担忧的问题。引起肠道感染的耐药病原体的出现加剧了人们的担忧，并促使人们呼吁开发不会产生耐药性的新型抗菌药物。角藻素对肠道病原体具有活性，并且口服耐受性良好。角藻素的临床应用步骤包括大规模合成、配方、毒性和功效研究。建议采取这些步骤。此外，特定的角藻蛋白对某些艰难梭菌临床分离株表现出非常高水平的活性，并且预计对角藻蛋白的微小修饰将产生针对这种人类病原体具有广泛的选择性活性的化合物。建议对与艰难梭菌膜的相互作用进行研究，并进行适度的结构活性研究，以更好地将角藻蛋白靶向艰难梭菌。相关性（参见说明）：目标生物体是志贺氏菌属。和艰难梭菌（包括耐药形式）。角藻素还对以下生物体具有活性：大肠杆菌、弧菌、沙门氏菌、单核细胞增生李斯特氏菌、空肠弯曲菌和小肠结肠炎耶尔森氏菌（所有 B 类病原体）。角锥菌素的研究和开发属于“先天免疫”领域，也被列为C类。