ANTIMICROBIALS AGAINST CHLAMYDIA AND GC INFECTION: IN VITRO STUDIES

针对衣原体和胃癌感染的抗菌药物：体外研究

• 批准号: 6663926
• 负责人: MORRIS D COOPER
• 金额: $ 18.05万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6663926
• 关键词: Chlamydia trachomatis; Neisseria gonorrhoeae; antibacterial agents; chlamydial disease; cholanate compound; detergents; disease /disorder prevention /control; drug screening /evaluation; genital secretion; gonorrhea; heparan sulfate; human tissue; mucopolysaccharides; sexually transmitted diseases; surfactant; tissue /cell culture; topical drug application; Chlamydia trachomatis; Neisseria gonorrhoeae; antibacterial agents; chlamydial disease; cholanate compound; detergents; disease /disorder prevention /control; drug screening /evaluation; genital secretion; gonorrhea; heparan sulfate; human tissue; mucopolysaccharides; sexually transmitted diseases; surfactant; tissue /cell culture; topical drug application

Microbial pathogens which invade the genital mucosa have specific mechanisms which involve adherence, invasion, intracellular survival and exit as a means of production of pathogenicity. C. trachomatis is the most common sexually transmitted bacterial pathogen in this country causing about 4.5 million cases of chlamydia in men, women, and children. The majority of chlamydial infections in women are asymptomatic, sequealae of untreated infections are an important part of the pathogenesis of the disease. Infections due to N. gonorrhoeae, like those of C. trachomatis, remain a major cause of STDs. Further, they remain a major cause of pelvic inflammatory disease, tubal infertility, ectopic pregnancy and chronic pelvic pain in the United States. Epidemiologic data provide strong evidence that gonococcal infections facilitate the transmission of other STDs and studies have begun to elucidate the specific mechanisms through which this facilitation occurs(). In 1996, there were greater than 325,000 cases of gonorrhea reported in the United States. However, this rate has continued to decline since 1975 but still remains a significant cause of disease. Although adequate antimicrobial therapy exists for this infection rates are high (17 percent/100,000 population) and antimicrobial resistance is significant (29 percent of all isolates collected in 1996 were resistant to penicillin, tetracycline or both). Therefore, alternate methods of controlling the infection remains a high priority. Toward this end, we are aggressively pursuing antimicrobials which have potential as topical microbicides. Therefore, there is a critical need to find a microbicide that would interact with these pathogens either prior to or at the point of interaction with cells of the genital mucosa. We have decided to study a variety of chemical agents including detergents, bile salts and other compounds to determine their antichlamydial and antigonococcal activity in both in vitro assays using cell cultures and the human fallopian tube organ culture model. This proposal will address several questions which are central to the determination of useful microbicidal agents which will interrupt the interaction between the chlamydial elementary body and/or gonococci and receptors on the host cell surface. The specific aims of this proposal are: (1) To expand the human primary cell culture systems to evaluate in vitro the efficacy and cytotoxicity of potential topical antimicrobials to prevent infection of the genital mucosa by Chlamydia trachomatis and/or Neisseria gonorrhoeae. (2) Define the mechanism(s) by which select non-cytotoxic candidate topical antimicrobials inhibit C. trachomatis and/or N. gonorrhoeae and (3) Isolate the HS glycosaminoglycans (GAGs) from human genital tract cells and organ cultures and identify fractions important for C. trachomatis adherence to cells. These studies should allow a detailed study of antimicrobials which will allow their potential as topical microbicides to be exploited.

侵入生殖器粘膜的微生物病原体具有特定的机制，涉及依从性，入侵，细胞内存活和退出作为致病性的产生手段。 沙眼梭状芽孢杆菌是该国最常见的性传播细菌病原体，在男性，女人和儿童中造成约450万例衣原体。 女性的大多数衣原体感染是无症状的，未经治疗的感染的后遗症，是该疾病发病机理的重要组成部分。 像沙眼梭状芽孢杆菌一样，由于淋病链球菌引起的感染仍然是性病的主要原因。 此外，它们仍然是美国盆腔炎症性疾病，输卵管不育症，异位妊娠和慢性骨盆疼痛的主要原因。流行病学数据提供了有力的证据，表明淋球菌感染有助于其他性病的传播，研究开始阐明了这种促进性的特定机制（）。 1996年，美国报告了32.5万例淋病。但是，自1975年以来，这种速度一直在下降，但仍然是疾病的重要原因。 尽管对于这种感染率而存在足够的抗菌治疗，但抗菌耐药性很高（1996年收集的所有分离株中，有29％对青霉素，四环素或两者兼而有之）。 因此，控制感染的替代方法仍然是很高的优先级。 为此，我们正在积极追求具有局部生体潜力的抗菌剂。因此，在与生殖器粘膜细胞相互作用之前或与这些病原体相互作用时，迫切需要找到与这些病原体相互作用的杀菌剂。 我们已决定研究各种化学剂，包括清洁剂，胆汁盐和其他化合物，以确定其在使用细胞培养物和人类输卵管器官培养模型的体外测定中，在两种体外测定中确定其抗裂解和抗巨球菌活性。 该提案将解决几个问题，这些问题对于确定有用的微生物剂的核心，这些问题将中断宿主细胞表面上的衣原体基本体与/或Gonococci和受体之间的相互作用。 该提案的具体目的是：（1）扩展人类原代细胞培养系统，以评估潜在局部抗菌剂的疗效和细胞毒性，以防止沙眼衣原体和/或酸诺氏菌的卫生性粘膜感染生殖器粘膜。 （2）定义了选择的机制，该机制通过该机制抑制沙眼梭状芽孢杆菌和/或淋病链球菌，并（3）隔离HS糖胺聚糖（GAGS），对人的生殖细胞和细胞培养物和识别小细胞和鉴定小细胞对小细胞的差异很重要。 这些研究应允许对抗菌药物进行详细研究，这将使它们作为局部杀菌剂的潜力得到利用。