Peptide Deformylase Inhibitor LBM415 for Sexually Transmitted Infections

用于性传播感染的肽去甲酰酶抑制剂 LBM415

• 批准号: 8707718
• 负责人: HUIZHOU FAN
• 金额: $ 1.93万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707718
• 关键词: Peptide; Deformylase; Inhibitor; LBM415; Sexually

DESCRIPTION (provided by applicant): This R21/R33 phased project will explore a novel strategy for combating sexually transmitted chlamydial and gonococcal infections. Chlamydia trachomatis and Neisseria gonorrhoeae are the most common sexually transmitted pathogens. In addition to acute urogenital inflammation, chlamydial and gonococcal infections frequently result in devastating complications including infertility and chronic pelvic pain syndrome. Infection with these bacteria also increases the risk of HIV infection. Sexually transmitted chlamydial and gonococcal infections disproportionately affect the wellness of women. Therefore, there is an urgent need to develop effective self-administered topical antimicrobials to combat the transmission of these organisms and other sexually transmitted pathogens. We have discovered that C. trachomatis and N. gonorrhoeae are highly susceptible to inhibitors of peptide deformylase (PDF), an enzyme that catalyzes the removal of the formyl group from newly synthesized proteins/peptides before they become biologically active. Lactobacilli and Escherichia coli are significantly resistant to PDF inhibitors. We hypothesize that PDF inhibitors may be used topically to prevent sexually transmitted chlamydial and gonococcal infections without disrupting normal microflora. The goal of the R21-phase research is to determine the feasibility of utilizing the lead PDF inhibitor LBM415 topically for combating genital chlamydial and gonococcal infections. Thus, mice will be intravaginally exposed to a commercial gel containing LBM415 to determine whether LBM415 is free of acute and long-term toxicity, and provides protection against vaginal chlamydial and/or gonococcal infections upon its topical application. In addition, the effects of LBM415 on vaginal probiotic lactobacilli and bacterial vaginosis-associated pathogens will be determined. Frequencies of resistance to LBM415 in Chlamydia trachomatis and N. gonorrhoeae will also be assessed. If the R21 research meets its defined milestones (i.e., meaningful protection against chlamydial and gonococcal infections in vivo, a lack of in vivo toxicity, significant toleration by probiotic lactobacilli and acceptable resistance frequencies), additional studies will be carried out to further determine the value of LBM415 for combating chlamydial and gonococcal infections in the R33 phase. During the R33 phase, dose-response, inhibition of pathogen shedding from animals with pre-established infection, possibility of "early" application and potential synergism with another promising broad-spectrum topical microbicide candidate will be studied.

描述（由申请人提供）：该R21/R33分阶段项目将探讨一种与性传播的衣原体和淋球菌感染对抗的新型策略。沙眼衣原体和淋病奈瑟氏菌是最常见的性传播病原体。除了急性泌尿生殖器炎症外，衣原体和淋球菌感染还经常导致毁灭性并发症，包括不育和慢性骨盆疼痛综合征。这些细菌感染也增加了HIV感染的风险。性传播的衣原体和淋球菌感染不成比例地影响妇女的健康。因此，迫切需要开发有效的自助局部局部抗微生物，以打击这些生物的传播和其他性传播的病原体。我们已经发现，沙眼梭状芽孢杆菌和淋病链球菌非常容易受到肽畸形酶抑制剂（PDF）的抑制剂，这是一种酶，可在它们从新近合成的蛋白质/肽中催化甲基从新近合成的蛋白质/肽中催化。乳杆菌和大肠杆菌对PDF抑制剂具有显着抗性。我们假设可以局部使用PDF抑制剂来防止性传播的衣原体和淋球菌感染而不会破坏正常的微生物。 R21相研究的目的是确定利用铅PDF抑制剂LBM415的可行性，以局部对抗生殖器衣原体和淋球菌感染。因此，将小鼠在腔内暴露于含有LBM415的商业凝胶中，以确定LBM415是否没有急性和长期毒性，并在其局部应用时提供了防止阴道衣原体和/或淋球菌感染的保护。此外，将确定LBM415对阴道益生菌乳酸杆菌和细菌性阴道病相关的病原体的影响。在沙眼衣原体和淋病链球菌中对LBM415的抗性频率也将进行评估。如果R21研究符合其定义的里程碑（即，对体内缺乏体内毒性缺乏对衣原体和淋球菌感染的有意义的保护，益生菌乳酸杆菌的耐受性很大，可接受的抵抗频率明显的耐受性），则将进一步确定其他研究的进一步研究，以进一步确定Chlam and Gon and chlam and lbm415 chlamy and gon chlamy and gon chlamy and gon chlamy cons and coption lcm415 R33阶段。在R33阶段，剂量反应，抑制具有预先建立的感染的动物的病原体脱落，“早期”应用的可能性以及潜在的协同作用，并研究了另一种有希望的广谱局部型杀伤力候选者。