Development of Novel Antimicrobial Peptide Mimics

描述(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。抗菌肽在控制包括胃肠道在内的多种组织中的细菌生长方面发挥着核心作用。抗菌肽在从人类到昆虫的各种有机体中都被发现，它们的无处不在表明它们已经独立进化了无数次。这一观察认为，它们消除细菌的机制为控制细菌生长提供了一种可持续的方法。然而，抗菌肽的大规模制备相对困难，通常它们是蛋白酶的底物。角蛋白的制备相对简单，因为它们不是基于多肽的，所以它们不是蛋白酶的底物。在对角蛋白和选定的抗菌肽的多重直接比较中，它们的作用机制是难以区分的。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潜在生物恐怖主义手段。引起肠道感染的抗药性病原体的出现加剧了这一担忧，并促使人们呼吁使用不会产生抗药性的新抗菌剂。Ceragenins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、毒性和有效性研究。提出了这些步骤。此外，特定的Ceragenins对艰难梭菌的某些临床分离株表现出非常高的活性，预计对Ceragenins的微小修改将产生对这种人类病原体具有广泛、选择性活性的化合物。建议对艰难梭菌与膜的相互作用进行研究，并进行适度的结构-活性研究，以更好地针对艰难梭菌的脑胶原蛋白。相关性(见说明书)：目标生物是志贺氏菌。艰难梭菌(包括耐药菌株)。角质蛋白对下列生物也有活性：大肠杆菌、弧菌、沙门氏菌、单核细胞增生性李斯特氏菌、空肠弯曲菌和小肠结肠炎耶尔森菌(均为B类致病菌)。角质蛋白的研究和开发属于也被列为C类的“先天免疫”领域。

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.