TOPICAL MICROBICIDES AND BIOLOGY OF VENEREAL PATHOGENS

外用杀菌剂和性病病原体的生物学

• 批准号: 2667758
• 负责人: Lawrence Raymond Stanberry
• 金额: $ 83.15万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-03-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2667758
• 关键词: antibacterial agents; antiviral agents; disease /disorder prevention /control; drug screening /evaluation; sexually transmitted diseases; topical drug application

Sexually transmitted diseases (STD) are a major public health problem worldwide. Control of this epidemic will require multiple approaches including vaccine development, increased use of barrier methods, improved patient education and development of new antimicrobial drugs. An important strategy that warrants exploration is the development of topical microbicides designed for intravaginal use and intended to prevent infection at the portal of entry. In this application we propose three projects designed to evaluate the in vitro and in vivo efficacy and toxicity of candidate microbicidal compounds and to further explore the pathogenesis of sexually transmitted viral (HSV and HIV) and bacterial (chlamydia) pathogens. We have selected a series of polysulfated carbohydrates and surface-active agents expected to have in vitro microbicidal activity. In Project 1 (Microbicidal agents for HSV and HIV-1: In vitro studies), Dr. Patricia Spear and her colleagues will determine the in vitro antiviral and cytotoxic activities of these candidate microbicides. Additionally they will construct HIV mutants and explore the role of envelope glycoproteins in initiating viral infection. They will also investigate HSV mutants and explore the role of envelope glycoproteins in initiating viral infection. They will also investigate HSV and HIV infection of primary human cells derived from the female reproductive tract and determine the ability of lead compounds to protect these cells. In Project 2 (Effects of microbicides on chlamydial infections) Dr. Morris Cooper will evaluate the antichlamydial activity and cellular cytotoxicity of the compounds in cell and human fallopian tube organ cultures. As a possible target for microbicidal action he will also examine the role of chlamydial glycosaminoglycan ligands in initiating infection of human genital epithelial cells. Microbicides found to have potent antimicrobial activity and low cellular toxicity in Projects 1 and 2 will be evaluated in Project 3 (Studies with animal models of STD) by Dr. Lawrence Stranberry to determine whether they can prevent genital HSV-2 or chlamydial infection in guinea pigs. Additional studies in project 3 are intended to increase our understanding of the pathogenesis of genital herpes and facilitate the development of chemoprophylactic approaches to the control of HSV infections. Compounds with in vivo activity (and in vitro activity against HIV) will be referred to the Toxicology Core, directed by Dr. Shirley Reising, for evaluation of their spermicidal activity, genital tract irritant effects, mucosal immunotoxicological properties and effects on fertility and vaginal flora. We expect this cooperative effort will identify broad spectrum intravaginal microbicides that will be safe and effective in women. In addition, these projects will yield new information regarding the pathobiology of HSV, HIV and chlamydia that will be useful in designing strategies to prevent sexually transmitted diseases.

性传播疾病（STD）是一个主要的公共卫生问题 全世界。 控制这种流行将需要多种方法 包括疫苗开发，增加屏障方法的使用，改善 新型抗菌药物的患者教育和开发。 一个重要的 需要探索的策略是局部的发展 旨在用于丢血的使用的菌皮，并旨在防止 进入门户的感染。 在此应用中，我们提出了三个 旨在评估体外和体内功效的项目 候选杀生化合物的毒性，并进一步探索 性传播病毒（HSV和HIV）和细菌的发病机理 （衣原体）病原体。 我们选择了一系列多硫化碳水化合物和表面活性 预计药物具有体外生液活性。 在项目1中 （HSV和HIV-1的杀生剂：体外研究），Patricia博士 长矛和她的同事将确定体外抗病毒和 这些候选微生物的细胞毒性活性。 另外他们 将构建HIV突变体并探索包膜糖蛋白的作用 在启动病毒感染时。 他们还将调查HSV突变体和 探索包膜糖蛋白在启动病毒感染中的作用。 他们还将研究原代人类细胞的HSV和HIV感染 源自女性生殖道，并确定 铅化合物可保护这些细胞。 在项目2中（效果 关于衣原体感染的微生物）莫里斯·库珀（Morris Cooper）博士将评估 细胞中化合物的抗氨活动和细胞细胞毒性 和人类输卵管器官文化。 作为可能的目标 他还将检查衣原体的作用 糖胺聚糖配体在启动人类生殖器感染时 上皮细胞。 发现具有有效抗菌活性的微生物 项目1和2中的细胞毒性低，将在项目中评估 3（使用STD动物模型的研究）劳伦斯·斯兰伯里博士 确定它们是否可以预防生殖器HSV-2或衣原体感染 豚鼠。 项目3中的其他研究旨在增加我们的 了解生殖器疱疹的发病机理并促进 开发用于控制HSV的化学预防方法 感染。 具有体内活性的化合物（以及对体外活性 艾滋病毒）将转介雪莉博士指导的毒理学核心 为了评估其精子活性，生殖道 刺激性作用，粘膜免疫毒性特性以及对 生育和阴道菌群。 我们预计这种合作的努力将确定广泛的弹药 对女性安全有效的微生物。 另外，这些 项目将产生有关HSV，艾滋病毒病理学的新信息 和衣原体将有助于设计策略以防止 性传播疾病。