Development of Novel Antimicrobial Peptide Mimics

描述（由申请人提供）：Ceragenins是内源性抗菌肽的小分子模拟物。它们是广谱抗微生物剂，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）中的细菌生长方面发挥着重要作用。从人类到昆虫的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一种控制细菌生长的可持续手段。然而，抗微生物肽相对难以大规模制备，并且通常它们是蛋白酶的底物。角鲨精制备相对简单，并且因为它们不是基于肽，所以它们不是蛋白酶的底物。在对ceragenins和选定的抗菌肽进行多重直接比较时，它们的作用机制是不可区分的。肠道感染每年导致数百万人死亡，阻碍数千万儿童的发育，延长住院时间，增加住院患者的死亡率，并已成为水和食物污染造成的生物恐怖主义的潜在手段，令人关切。引起肠道感染的耐药病原体的出现加剧了这一关切，并促使人们呼吁开发不会产生耐药性的新抗菌剂。角鲨精对肠道病原体有活性，口服耐受性良好。走向临床应用的步骤包括大规模的合成，配方，毒性和疗效研究。提出了这些步骤。此外，特异性的角鲨烷皂苷对艰难梭菌的某些临床分离株显示出非常高水平的活性，并且预期对角鲨烷皂苷的微小修饰将产生对该人类病原体具有广泛选择性活性的化合物。研究了C. difficile和适度的结构-活性研究提出了更好地靶向C.很难相关性（见说明书）：目标微生物为志贺氏菌属。和C.艰难梭菌（包括耐药形式）。角鲨精还对以下生物体具有活性：E.大肠杆菌、弧菌、沙门氏菌、单核细胞增生李斯特菌、空肠弯曲杆菌和小肠结肠炎耶尔森氏菌（所有B类病原体）。研究和开发的ceragenins福尔斯“先天免疫”领域，也被列入C类。

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.