MODELS FOR TESTING CANDIDATE TOPICAL MICROBICIDES FOR CYTOTOXICITY AND ACTIVITY A

描述(申请人提供)：沙眼衣原体是一种专性细胞内寄生虫，是世界上最常见的性传播细菌病原体。感染通常是无症状的，可能会导致严重的并发症，如盆腔炎、不孕症和异位妊娠。此外，衣原体感染可能会增加人类免疫缺陷病毒(HIV)传播的风险。用于防止性传播感染的局部杀微生物剂的开发最近得到了关注。我们建立了体外最低杀灭浓度(MCC)试验，以测试杀菌剂对胞外感染性衣原体EBS的直接作用。我们现在建议通过研究多肽和脂类局部杀菌剂的体外安全性和有效性，以及菌株变异和人血清白蛋白、模拟阴道液或模拟精液的存在的影响，继续发展MCC试验。MCC试验将进一步用于分析与通用安慰剂单独或联合使用的新型抗菌剂对沙眼衣原体的活性。最后，我们将在非人类灵长类动物模型中检查安全和有效的候选局部杀微生物剂的选定配方，以了解阴道和直肠的安全性和有效性。将评估抗衣原体杀菌剂对机体的作用方式，以及沙眼衣原体菌株对所选杀菌剂产生抗药性的可能性。通过提供其他实验室无法提供的这些高度专业化的实验室测试和专业知识，衣原体实验室将从根本上促进局部杀微生物剂研究，这最终将有助于预防世界各地的艾滋病毒和衣原体感染。

DESCRIPTION (provided by applicant): Chlamydia trachomatis, an obligate intracellular parasite, is the most common sexually transmitted bacterial pathogen in the world. Infections are often asymptomatic and can cause serious complications such as pelvic inflammatory disease, infertility, and ectopic pregnancy. In addition, chlamydial infections may increase the risk of human immunodeficiency virus (HIV) transmission. The development of topical microbicides to prevent sexually transmitted infections has recently gained attention. We have developed the in vitro minimal cidal concentration (MCC) assay to test the direct action of microbicides on the extracellular, infectious chlamydial EBs. We now propose to continue developing the MCC assay by studying the in vitro safety and efficacy of peptide and lipid topical microbicides and the effects of strain variation and the presence of human albumin, simulated vaginal fluid, or simulated semen. The MCC assay will further be employed to analyze the effect of novel antimicrobial agents, placed in formulation with universal placebo singly or in combination, for their activity against C. trachomatis. Finally, we will examine safe and active selected formulations of candidate topical microbicides in vivo in a non-human primate model for vaginal and rectal safety and efficacy. The mode of action of anti-chlamydial microbicides on the organism will be assessed as well as the possibility of C. trachomatis strains developing resistance to the selected microbicides. By providing these highly specialized laboratory tests and expertise not readily available in other laboratories, the chlamydia laboratory will contribute fundamentally to topical microbicide research which will ultimately help to prevent HIV and chlamydial infections around the world.