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人，念珠菌病可导致口腔局部但疼痛的病变，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非白色念珠菌（NAC）引起的。因此，开发既能治疗白色念珠菌感染又能治疗NAC引起的感染的新疗法至关重要。抗菌肽（AMPs）是天然存在的广谱抗菌药物，近年来作为治疗性抗生素和抗真菌药物被研究。它们的主要优点是微生物通常不会对这些药物产生耐药性。不幸的是，它们的生产成本很高，而且往往对蛋白酶消化很敏感。Polymedix公司开发了一系列廉价的非肽低聚物和聚合物，它们在结构和活性上都模仿amp。在该资助的第一阶段，我们研究了一系列AMPs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先导物的潜力。我们的研究结果表明，在浮游生物和生物膜培养中，几种模拟物对白色念珠菌和非白色念珠菌都有有效的活性。活性快，对孢子分生孢子和菌丝均有杀真菌作用。我们也未能产生耐药念珠菌菌株，证实它们作为抗念珠菌药物有吸引力的候选者的价值。为了继续开发候选菌活性模拟物，我们提出了以下第二阶段应用的目标：建立口腔念珠菌感染小鼠模型。2)确定I期鉴定的肽模拟化合物在体内对口腔念珠菌感染的活性。3)优化模拟化学，获得最活性的化合物。我们在这一阶段的总体目标是确定最佳化合物和条件下，抗菌肽模拟物可以应用于口腔黏膜，以有效清除实验性念珠菌感染。该阶段的成功完成将为进一步开发作为口腔念珠菌病局部治疗的主要候选药物提供支持。

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.