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: 2074843
• 负责人: Lawrence Raymond Stanberry
• 金额: $ 44.96万
• 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 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2074843
• 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）是一个重大的公共卫生问题 全世界。 控制疫情需要多管齐下 包括疫苗开发、增加屏障方法的使用、改进 患者教育和新抗菌药物的开发。 一个重要的 值得探索的策略是开发主题 专为阴道内使用而设计的杀菌剂，旨在预防 入口处感染。 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 候选杀菌化合物的毒性并进一步探讨 性传播病毒（HSV 和 HIV）和细菌的发病机制 （衣原体）病原体。 我们精选了一系列多硫酸化碳水化合物和表面活性剂 预期具有体外杀菌活性的试剂。 在项目1中 （HSV 和 HIV-1 杀菌剂：体外研究），Patricia 博士 斯皮尔和她的同事将确定体外抗病毒和 这些候选杀微生物剂的细胞毒活性。 另外他们 将构建HIV突变体并探索包膜糖蛋白的作用 启动病毒感染。 他们还将研究 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 来自女性生殖道并确定 铅化合物来保护这些细胞。 在项目 2 中（的影响 衣原体感染的杀菌剂）莫里斯·库珀博士将评估 化合物在细胞中的抗衣原体活性和细胞毒性 和人类输卵管器官培养。 作为一个可能的目标 杀菌作用他还将检查衣原体的作用 糖胺聚糖配体启动人类生殖器感染 上皮细胞。 发现杀菌剂具有有效的抗菌活性 项目1和2的低细胞毒性将在项目中进行评估 3（STD 动物模型研究）Lawrence Stranberry 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 中的其他研究旨在提高我们的 了解生殖器疱疹的发病机制，促进治疗 开发控制 HSV 的化学预防方法 感染。 具有体内活性（以及体外活性）的化合物 HIV）将被转介至由 Shirley 博士指导的毒理学核心 Reising，用于评估其杀精活性、生殖道 刺激作用、粘膜免疫毒理学特性以及对 生育能力和阴道菌群。 我们预计这种合作努力将确定广谱阴道内 对女性安全有效的杀菌剂。 此外，这些 项目将产生有关 HSV、HIV 病理学的新信息 和衣原体，这将有助于设计预防策略 性传播疾病。