Peptide Deformylase Inhibitor LBM415 for Sexually Transmitted Infections

描述(由申请人提供)：这个R21/R33分阶段项目将探索抗击性传播衣原体和淋球菌感染的新战略。沙眼衣原体和淋病奈瑟菌是最常见的性传播病原体。除了急性泌尿生殖道炎外，衣原体和淋球菌感染经常导致毁灭性的并发症，包括不孕不育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。性传播衣原体和淋球菌感染对妇女的健康造成不成比例的影响。因此，迫切需要开发有效的自我给药局部抗菌剂，以对抗这些微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球菌对多肽变形酶(PDF)的抑制剂高度敏感，多肽变形酶是一种在新合成的蛋白质/多肽具有生物活性之前催化去除甲酰基的酶。乳酸菌和大肠埃希菌对PDF抑制剂具有显著的耐药性。我们推测，PDF抑制剂可以在不破坏正常菌群的情况下，局部使用来预防性传播的衣原体和淋球菌感染。R21阶段研究的目标是确定局部使用主要的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，小鼠将在阴道内暴露于含有LBM415的商业凝胶中，以确定LBM415是否没有急性和长期毒性，并在局部使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对阴道益生菌乳杆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的耐药性频率。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、对益生菌乳杆菌的显著耐受性和可接受的耐药性频率)，将进行额外的研究，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、抑制预先确定感染的动物的病原体脱落、“早期”应用的可能性以及与另一种有前景的广谱局部杀微生物剂候选药物的潜在协同作用。

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.