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: 7500749
• 负责人: HUIZHOU FAN
• 金额: $ 19.66万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500749
• 关键词: Acute; Affect; Animals; Antibiotics; Bacteria; Bacterial Vaginosis; BufferGel; Cells; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Clinical Trials; Dose; Drug Formulations; Enzymes; Escherichia coli; Estradiol; Excision; Female; Frequencies; Gel; Genital system; Genitourinary system; Goals; Gonorrhea; HIV Infections; Human; Inbred BALB C Mice; Infection; Infertility; Inflammation; LBM415; Lactobacillus; Lead; Local Microbicides; Medroxyprogesterone; Modification; Mus; Mutation; Neisseria gonorrhoeae; Organism; Peptides; Phase; Pneumonia; Probiotics; Proteins; Research; Resistance; Risk; Safety; Self-Administered; Sexually Transmitted Diseases; Source; Standards of Weights and Measures; Swab; Time; Topical application; Toxic effect; Vagina; Woman; Work; antimicrobial; chronic pelvic pain; cofactor; day; in vivo; inhibitor/antagonist; irritation; microbicide; novel strategies; pathogen; peptide deformylase; prevent; response; synergism; transmission process; vaginal lactobacilli

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。除了急性泌尿生殖道炎症外，衣原体和淋球菌感染还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。这些细菌的感染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严重影响女性的健康。因此，迫切需要开发有效的自我施用局部抗菌剂来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病奈瑟菌对肽去甲酰基酶 (PDF) 抑制剂高度敏感，这种酶在新合成的蛋白质/肽变得具有生物活性之前催化去除甲酰基。乳酸杆菌和大肠杆菌对 PDF 抑制剂具有显着的耐药性。我们假设 PDF 抑制剂可局部用于预防性传播衣原体和淋球菌感染，而不破坏正常微生物群落。 R21 阶段研究的目标是确定局部利用主要 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，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针对阴道衣原体和/或淋球菌感染的保护。此外，还将确定 LBM415 对阴道益生菌乳酸杆菌和细菌性阴道病相关病原体的影响。沙眼衣原体和淋病奈瑟菌对 LBM415 的耐药频率也将被评估。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具有有意义的保护、缺乏体内毒性、益生菌乳杆菌显着耐受以及可接受的耐药频率），将进行额外的研究，以进一步确定 LBM415 在对抗衣原体和淋球菌感染方面的价值 R33相。在R33阶段，将研究剂量反应、对预先感染的动物排出病原体的抑制、“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。

项目成果

Lactobacilli inactivate Chlamydia trachomatis through lactic acid but not H2O2.

• DOI: 10.1371/journal.pone.0107758
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gong Z;Luna Y;Yu P;Fan H
• 通讯作者: Fan H

High tolerance to mutations in a Chlamydia trachomatis peptide deformylase loop.

• DOI: 10.4331/wjbc.v2.i5.90
• 发表时间: 2011-05-26
• 期刊: World journal of biological chemistry
• 作者: Oey, Christopher B;Bao, Xiaofeng;Fan, Huizhou
• 通讯作者: Fan, Huizhou

Exploration of chlamydial type III secretion system reconstitution in Escherichia coli.

• DOI: 10.1371/journal.pone.0050833
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bao X;Beatty WL;Fan H
• 通讯作者: Fan H

Chloramphenicol acetyltransferase as a selection marker for chlamydial transformation.

• DOI: 10.1186/1756-0500-6-377
• 发表时间: 2013-09-23
• 期刊: BMC research notes
• 影响因子: 1.8
• 作者: Xu S;Battaglia L;Bao X;Fan H
• 通讯作者: Fan H

Non-coding nucleotides and amino acids near the active site regulate peptide deformylase expression and inhibitor susceptibility in Chlamydia trachomatis.

• DOI: 10.1099/mic.0.049668-0
• 发表时间: 2011-09
• 期刊: Microbiology (Reading, England)
• 作者: Bao X;Pachikara ND;Oey CB;Balakrishnan A;Westblade LF;Tan M;Chase T;Nickels BE;Fan H
• 通讯作者: Fan H