Peptide Deformylase Inhibitor LBM415 for Sexually Transmitted Infections

描述（由申请人提供）：这个R21/R33阶段的项目将探索一种对抗性传播衣原体和淋球菌感染的新策略。沙眼衣原体和淋病奈瑟菌是最常见的性传播病原体。除了急性泌尿生殖系统炎症外，衣原体和淋球菌感染经常导致毁灭性的并发症，包括不孕症和慢性盆腔疼痛综合征。感染这些细菌也会增加感染艾滋病毒的风险。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我给药局部抗菌剂，以对抗这些生物和其他性传播病原体的传播。我们发现沙眼衣原体和淋病奈瑟菌对肽去甲酰基酶（PDF）抑制剂高度敏感，肽去甲酰基酶是一种催化新合成的蛋白质/肽在其具有生物活性之前去除甲酰的酶。乳酸菌和大肠杆菌对PDF抑制剂有明显的抗性。我们假设PDF抑制剂可以局部用于预防性传播的衣原体和淋球菌感染，而不会破坏正常的微生物群。r21期研究的目标是确定局部使用先导PDF抑制剂LBM415对抗生殖器衣原体和淋球菌感染的可行性。因此，将小鼠阴道内暴露于含有LBM415的商业凝胶中，以确定LBM415是否没有急性和长期毒性，并在局部应用时提供对阴道衣原体和/或淋球菌感染的保护。此外，还将确定LBM415对阴道益生菌乳酸菌和细菌性阴道病相关病原体的影响。还将评估沙眼衣原体和淋病奈瑟菌对LBM415的耐药频率。如果R21研究达到其定义的里程碑（即对体内衣原体和淋球菌感染有意义的保护，缺乏体内毒性，益生菌乳酸菌的显著耐受性和可接受的耐药频率），将进行进一步的研究，以进一步确定LBM415在R33阶段对抗衣原体和淋球菌感染的价值。在R33阶段，将研究剂量反应、对预先感染动物病原体脱落的抑制、“早期”应用的可能性以及与另一种有前途的广谱局部杀菌剂候选物的潜在协同作用。

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.