Biomimetic antimicrobials for biowarfare pathogens

描述（由申请人提供）：CDC已经确定了一些细菌作为潜在的生物战剂。目前控制生物恐怖袭击后感染的战略是通过使用抗菌剂进行预防和治疗。这一战略面临的最大挑战是自然产生的耐药性的存在，以及许多生物战菌株中工程耐药性的表现。因此，迫切需要开发新的抗菌剂，其可以逃避与发展耐药菌株相关的分子机制和宿主反应。PolyMeidine目前正在开发一系列非肽类化合物，这些化合物独特地适用于针对生物战生物的治疗和材料应用。这些仿生化合物模拟蛋白质的关键生物学特性，并且比天然蛋白质更稳定，生产成本更低。这项技术的第一个应用是设计和合成宿主防御肽的非肽模拟物，这些肽在健康中起着关键作用，作为对抗各种微生物的第一线攻击。相对于其天然存在的对应物，模拟物明显更小且更容易制备，因为等效且具有广泛活性。然而，非肽模拟物对人红细胞的毒性显著降低，制备成本低得多，并且应该更稳定。此外，所述化合物在聚合物形式中以及当施加到固体表面或掺入塑料如聚氨酯中时保持其抗微生物活性。重要的是，因为这些化合物模拟宿主防御肽的结构和生物活性，所以细菌耐药菌株的出现是非常不可能发生的。目前，已经合成了八类模拟物，通过其分子骨架的化学组成来区分，并测试了其抗微生物活性。I期研究的目的是鉴定以下化合物：1）杀死广谱生物战剂，对哺乳动物细胞无细胞毒性; 2）显示出对生物战病原体抗菌应用重要的机械特性;快速杀菌活性和细菌耐药性发生率低。这些研究将提供关于当前化合物系列对生物战生物的抗菌活性的关键概念验证信息。在第二阶段，将对第一代先导化合物进行彻底的先导化合物优化，以便随后开发特定的治疗和材料应用。

DESCRIPTION (provided by applicant): The CDC has identified a number of bacteria as potential biowarfare agents. A current strategy to control infections following a bioterroristic attack is through the use of antimicrobial agents for both prophylactic and therapeutic purposes. The most significant challenge to this strategy is the presence of naturally-occurring drug resistance and the demonstrated ease of engineering drug-resistance in many biowarfare strains. Therefore, there is a strong need for the development of new antibacterial agents that can evade molecular mechanisms and host responses associated with the development drug resistant strains. PolyMedix is presently developing a series of nonpeptidic compounds that are uniquely suited for therapeutic and material applications against biowarfare organisms. These biomimetic compounds mimic key biological properties of proteins, and are more stable and inexpensive to produce than natural proteins. The first application of this technology has been the design and synthesis of non-peptidic mimetics of host defense peptides that play a critical role in health, serving as a first line of attack against a wide range of microbes. In relation to their naturally occurring counterparts, the mimetics are significantly smaller and easier to prepare, as equipotent and as broadly active. However, the non-peptidic mimetics are significantly less toxic towards human erythrocytes, much less expensive to prepare, and should be much more stable. Furthermore, the compounds retain their antimicrobial activity in polymeric forms, and when applied to solid surfaces or incorporated into a plastic such as polyurethane. Importantly, because these compounds mimic the structure and biological activity of host defense peptides, the appearance of bacterial resistant strains is very unlikely to occur. Presently, eight classes of mimetics, distinguished by the chemical composition of their molecular backbone, have been synthesized and tested for antimicrobial activity. The goal of the Phase I studies is to identify compounds that 1) kill a broad spectrum of biowarfare agents and are not cytotoxic for mammalian cells 2) display mechanistic properties important for antimicrobial applications against biowarfare pathogens; rapid bactericidal activity and low incidence for the development of bacterial resistance. These studies will provide critical proof-of-concept information on the antimicrobial activities of the current compound series against the biowarfare organisms. In Phase II, thorough lead optimization will be done on the first generation lead compounds for subsequent development of specific therapeutic and material applications.