CANDIDACIDAL MECHANISMS OF SALIVARY HISTATINS

唾液组氨酸的抗念珠菌机制

• 批准号: 6634626
• 负责人: Mira Edgerton
• 金额: $ 19.64万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-03-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634626
• 关键词: Candida albicans; antifungal agents; calcium flux; calorimetry; candidiasis; cell membrane; chemical structure function; chemical substitution; circular dichroism; drug screening /evaluation; ergosterol; glycoproteins; high performance liquid chromatography; histidine; human tissue; intermolecular interaction; liposomes; membrane activity; membrane lipids; protein purification; protein structure function; protoplast /spheroplast; saliva; synthetic peptide; tissue /cell culture

DESCRIPTION (adapted from the Investigator's abstract): Incidence of oropharyngeal candidiasis has risen dramatically due to increased antibiotic usage and longer survival of individuals with compromised immune systems including patients on cancer chemotherapy, diabetics, AIDS patients and premature infants. Relatively few antifungal drugs are available for clinical treatment of oral or systemic candidiasis. Increased use of these agents to treat candidiasis in late stage AIDS and cancer patients has resulted in emergence of Candidal species with antifungal drug resistance, especially to azole-based drugs. Histatins (Hsts) are small cationic polypeptides produced by human major salivary glands. In vitro, Hst 5 is the most potent candidacidal member of the family which kills 90% to 100% of Candida species at physiological concentrations. Hsts' potent antifungal activity, lack of toxicity to humans and ability to kill azole-resistant yeast strains underscore the importance of detailed understanding of their mechanism of action. Improvements in candidacidal function of Hsts and development of oral Hst delivery systems also require information about the Hst-induced cascade of cellular events leading to C. albicans death. Previous studies showed that Hst mechanism of action is unique from other characterized antimycotic drugs in that induction of lethal effect is through a novel pathway initiated by ATP efflux from C. albicans cells, which occurs while the cell membrane is intact. Studies are proposed to examine related properties of Hst-induced ATP release, its cellular effects following Hst-induced ATP release leading to cell death, requirements for intracellular transport of Hst for candidacidal activity and examine potential involvement of cAMP, ABC transporters and purinergic receptors in C. albicans response to Hst 5. These studies will contribute to characterization of novel intracellular pathways utilized by Hst to cause yeast cell death and lead to further understanding of the role of ATP efflux as a cell regulatory or signaling process.

描述（改编自研究者摘要）： 由于抗生素的增加， 免疫系统受损的个体的使用和更长的生存期 包括癌症化疗患者、糖尿病患者、艾滋病患者， 早产儿相对较少的抗真菌药物可用于临床 治疗口腔或全身念珠菌病。增加使用这些药物， 治疗晚期艾滋病和癌症患者的念珠菌病， 出现了具有抗真菌药物抗性的真菌物种，特别是对 唑类药物组胺素（Hsts）是由组胺产生的小的阳离子多肽。 人的大唾液腺在体外，Hst 5是最有效的杀念珠菌剂， 该家族的一员，杀死90%至100%的念珠菌属物种， 生理浓度。Hsts的强效抗真菌活性，缺乏 对人类的毒性和杀死耐唑酵母菌株的能力强调， 详细了解其作用机制的重要性。 Hst杀念珠菌功能的改进和口服Hst的开发 传递系统还需要关于Hst诱导的级联反应的信息。 细胞事件导致C.白色念珠菌死亡。以前的研究表明，Hst 作用机制与其他特征性抗真菌药物不同， 致死效应的诱导是通过ATP启动的新途径， 外排C.白色念珠菌细胞，发生时细胞膜是完整的。 提出了研究Hst诱导的ATP释放的相关性质， 其在Hst诱导的ATP释放后的细胞效应导致细胞死亡， 对Hst细胞内转运以产生杀念珠菌活性的要求， 检查cAMP、ABC转运蛋白和嘌呤能蛋白的潜在参与 C.白色念珠菌对Hst的反应5.这些研究将有助于 Hst利用的新的细胞内途径的表征， 细胞死亡，并导致进一步了解ATP流出的作用， 细胞调节或信号传导过程。