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

基本信息

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
项目类别：
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

项目摘要

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，将小鼠阴道内暴露于含有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其价值LBM415 在 R33 阶段对抗衣原体和淋球菌感染。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

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chlamydia trachomatis protein GrgA activates transcription by contacting the nonconserved region of ýý66.

沙眼衣原体蛋白 GrgA 通过接触 α66 的非保守区域来激活转录。

DOI：
发表时间：
2012-10-16
期刊：
影响因子：
11.1
作者：
Bao, Xiaofeng;Nickels, Bryce E;Fan, Huizhou
通讯作者：
Fan, Huizhou

Regulation of chlamydial infection by host autophagy and vacuolar ATPase-bearing organelles.

宿主自噬和携带液泡 ATP 酶的细胞器对衣原体感染的调节。

DOI：
发表时间：
2011-10
期刊：
影响因子：
3.1
作者：
Yasir, Muhammad;Pachikara, Niseema D;Bao, Xiaofeng;Pan, Zui;Fan, Huizhou
通讯作者：
Fan, Huizhou

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

对沙眼衣原体肽去酰化酶环突变具有高耐受性。

DOI：
发表时间：
2011-05-26
期刊：
影响因子：
0
作者：
Oey, Christopher B;Bao, Xiaofeng;Lewis, Christal;Kerrigan, John E;Fan, Huizhou
通讯作者：
Fan, Huizhou

Benzylidene acylhydrazides inhibit chlamydial growth in a type III secretion- and iron chelation-independent manner.

亚苄基酰肼以 III 型分泌和铁螯合独立的方式抑制衣原体生长。

DOI：
发表时间：
2014-08-15
期刊：
影响因子：
3.2
作者：
Bao, Xiaofeng;Gylfe, Asa;Sturdevant, Gail L;Gong, Zheng;Xu, Shuang;Caldwell, Harlan D;Elofsson, Mikael;Fan, Huizhou
通讯作者：
Fan, Huizhou

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

大肠杆菌中衣原体 III 型分泌系统重建的探索。