A Novel Antimicrobial Mimetic for Oral Candidiasis

描述(由申请人提供)：口腔白色念珠菌感染是人类健康中一个日益严重的问题。在免疫功能受损的人中，尤其是那些患有艾滋病的人，念珠菌病可能会导致口腔局部但疼痛的损害以及危及生命的系统性感染。此外，由于使用了标准的抗真菌治疗，越来越多的感染是由非白念珠菌(NAC)引起的。因此，开发既能治疗白色念珠菌感染又能治疗由NAC引起的感染的新疗法至关重要。抗菌肽(AMPs)是一种天然存在的广谱抗菌剂，最近因其作为治疗性抗生素和抗真菌药物的用途而受到研究。它们的主要优势之一是，微生物通常不会对这些药物产生抗药性。不幸的是，它们的生产成本很高，而且往往对蛋白酶消化敏感。Polymedix，Inc.开发了一系列廉价的非肽齐聚物和聚合物，在结构和活性上都模拟AMPS。在这笔赠款的第一阶段，我们检查了一系列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先导的潜力。我们的结果表明，在浮游和生物膜培养中，这些模拟物的几类化合物对白色念珠菌和非白色念珠菌都具有很强的活性。活性快，对芽孢子体和菌丝形态均有杀菌作用。我们也未能产生耐药的念珠菌菌株，证明它们作为抗念珠菌药物的有吸引力的候选药物的价值。为了继续发展假丝酵母菌活性模拟，我们为这一阶段的应用提出了以下目标：1)。建立小鼠口腔念珠菌感染模型。2)确定I相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，获得活性最高的化合物。我们在这一阶段的总体目标是确定最佳化合物(S)和条件，在此条件下，抗菌肽模拟物可以应用于口腔粘膜，以有效清除实验中的念珠菌感染。这一阶段的成功完成将为进一步开发作为口腔念珠菌病的局部治疗药物提供一名领先的候选人(S)。 与公共卫生相关：口腔念珠菌感染是在免疫功能受损的人中发现的严重并发症，如艾滋病患者。开发安全有效的药物来治疗这些痛苦的、有时甚至危及生命的感染，而不会产生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测第一阶段确定的几种化合物对念珠菌的活性，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.