A Novel Antimicrobial Mimetic for Oral Candidiasis

描述（由申请方提供）：白色念珠菌的口腔感染代表了人类健康中日益严重的问题。在免疫功能低下的个体中，特别是那些患有艾滋病的个体中，念珠菌病可导致口腔中局部但疼痛的病变以及危及生命的全身感染。此外，由于使用标准的抗真菌治疗，越来越多的感染是由于非白色念珠菌（NAC）物种。因此，关键是要开发新的疗法，可以治疗这两个C。白色念珠菌感染以及NAC引起的感染。抗菌肽（Antimicrobial Peptides，AMP）是一类天然存在的广谱抗菌剂，近年来被广泛应用于抗生素和抗真菌药物的研究。它们的主要优点是微生物通常不会对这些试剂产生耐药性。不幸的是，它们的生产成本很高，并且通常对蛋白酶消化敏感。Polymedix，Inc.已经开发了一系列廉价的非肽寡聚物和聚合物，在结构和活性上模拟AMP。在第一阶段，我们研究了一系列AMP的小分子非肽模拟物，并评估了它们作为口腔念珠菌病局部治疗的潜在可能性。我们的结果表明，几类这些模拟物对C。白色念珠菌以及非白色念珠菌物种。活性迅速，对芽生孢子和菌丝都有杀菌作用。我们也未能产生耐药菌株的念珠菌，证实其作为抗念珠菌药物的有吸引力的候选人的价值。为了继续开发念珠菌活性模拟物，我们提出了该2期申请的以下目标：1）。小鼠口腔念珠菌感染模型的建立。2)确定在I期鉴定的肽模拟化合物对口腔念珠菌感染的体内活性。3)优化模拟化学以获得最具活性的化合物。我们在这一阶段的总体目标是确定最佳化合物和条件，在此条件下，抗菌肽模拟物可以应用于口腔粘膜，以有效地清除实验念珠菌感染。该阶段的成功完成将为进一步开发口腔念珠菌病的局部治疗提供开发领先候选药物。 公共卫生相关性：口腔念珠菌感染是在免疫功能低下的个体中发现的严重并发症，例如患有艾滋病的个体。开发安全有效的药物来治疗这些痛苦的，有时危及生命的感染，而没有发展念珠菌耐药菌株的风险，是至关重要的。我们建议在口腔念珠菌病的动物模型中检查在第一阶段确定的对念珠菌有活性的几种化合物，为开发这种疾病的治疗方法提供基础。

DESCRIPTION (provided by applicant): Oral infections of Candida albicans represent an increasing problem in human health. In immunocompromised individuals, especially those suffering from AIDS, candiasis can result in both localized, yet painful lesions in the oral cavity as well as life-threatening systemic infections. Furthermore, due to the use of standard antifungal treatments, an increasing number of infections are due to non-albicans candidal (NAC) species. It is thus critical to develop new therapies that can treat both C. albicans infections as well as those due to NAC. Antimicrobial peptides (AMPs) are naturally occurring, broad-spectrum antimicrobial agents that have been examined recently for their utility as therapeutic antibiotics and antifungals. Chief among their strengths is that microbes do not generally develop resistance to these agents. Unfortunately, they are expensive to produce and are often sensitive to protease digestion. Polymedix, Inc. has developed a series of inexpensive nonpeptidic oligomers and polymers that mimic AMPs in both structure and activity. In the first phase of this grant, we examined a series of small molecule non-peptide mimics of AMPs and evaluated their potential as leads for a topical treatment for oral candidiasis. Our results demonstrated the potent activity of several classes of these mimetics against C. albicans as well as non-albicans species in both planktonic and biofilm cultures. The activity was rapid, and fungicidal against both blastoconidia and hyphal forms. We have also failed to generate resistant strains of Candida, substantiating their value as attractive candidates for anti-candidal drugs. To continue the development of candida-active mimetics, we propose the following aims for this Phase 2 application: 1). Establish a mouse model of oral candidal infection. 2) Define the activity of peptide mimetic compounds identified in phase I on oral candidal infection in vivo. 3) Optimize the mimetic chemistry to achieve the most active compound. Our overall goal in this phase is to determine the optimal compound(s) and conditions under which an antimicrobial peptide mimetic can be applied to oral mucosa in order to efficiently clear an experimental Candida infection. Successful completion of this phase will provide a development lead candidate(s) for further development as a topical treatment for oral candidiasis. PUBLIC HEALTH RELEVANCE: Oral candidal infections are serious complications found in immunocompromised individuals, such as those suffering from AIDS. Development of safe and effective agents to treat these painful and sometimes life-threatening infections, without the risk of developing resistant strains of Candida, is essential. We propose to examine several compounds determined in the first phase to be active against Candida, in an animal model of oral candidiasis to provide the basis for development of a treatment for this disease.