Inhibitors of Nitro Drug Targets as Antimicrobials against Trichomonas Vaginalis

硝基药物靶点抑制剂作为阴道毛滴虫抗菌药物

基本信息

批准号：
9089977
负责人：
Patricia Jean Johnson
金额：
$ 20.79万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089977
关键词：
4-nitroimidazole Affect Alkynes Amebiasis American Antibiotics Bacterial Infections Biotin Cells Chemistry Chromatography Clinical Contracts Drug Targeting Drug resistance Drug usage Essential Drugs Essential Genes FDA approved Frequencies Genes Genitourinary system Genotype Geographic Locations Giardiasis Goals HIV Health Human In Vitro Incidence Infection Knock-out Laboratories Libraries Licensing Link Malignant neoplasm of cervix uteri Malignant neoplasm of prostate Mammalian Cell Mass Spectrum Analysis Methods Metronidazole Metronidazole resistance Microbe Modeling Parasites Parasitic infection Pharmaceutical Preparations Pharmacotherapy Phase Prevalence Prodrugs Proteins Research Resistance Risk Severities Sexually Transmitted Diseases Streptavidin System Testing Tetracyclines Tinidazole Trichomonas Infections Trichomonas vaginalis Urethritis Vaginitis adduct adverse pregnancy outcome antimicrobial base cell killing effective therapy fighting genetic analysis in vitro activity in vivo inhibitor/antagonist killings microbial new therapeutic target resistant strain reverse genetics therapy resistant transmission process

项目摘要

DESCRIPTION (provided by applicant): The unicellular parasite Trichomonas vaginalis is responsible for the most prevalent, non-viral, sexually-transmitted infection worldwide, with approximately 1/4 billion people contracting trichomoniasis annually. Trichomoniasis is the most common parasitic infection in the US and has an annual incidence estimated at 5 million cases. The frequency of infection and an increase in the number of drug resistant clinical isolates of T. vaginalis underscore the need to develop new chemotherapeutic strategies and drugs that eliminate the parasite. Resistance to the only drugs licensed for therapy, the 5-nitroimidazole (5NI) drugs metronidazole (Mz) and tinidazole (Tz), occurs in approximately 5% of cases of trichomoniasis. 5NIs are prodrugs that are activated by selective reduction inside anaerobic microbes, a step that is critical for killing, but also responsible for resistance when the microbe loses its capacity to reduce 5NIs. Upon activation, 5NIs kill the cell by forming covalent, inactivating adducts with essential target molecules, which are poorly defined. The long-term goal of the research proposed here is to define microbial targets of 5NI drugs that are essential for the survival of T. vaginalis and leverage this information to develop inhibitors of protein targets that are effective in the treatment of drug resistant trichomoniasis. The proposed studies have five Specific Aims. The first two aims will be achieved during the R21 phase and the latter three during the R33 phase. In Aim 1, we will identify nitro drug targets in model T. vaginalis strains using a strategy that employs click chemistry and mass spectrometry. In Aim 2, we will determine which protein targets are essential for T. vaginalis viability using reverse genetics to test whether elimination of the gene is lethal. After transitioning to the R33 phase, in Aim 3 we will identify nitro drug targets that are common to a broad range of geographically and genetically diverse T. vaginalis clinical isolates. In Aim 4, we will determine whether selected, common targets identified in Aim 3 are required for parasite viability. In Aim 5 we will develop inhibitors for the most promising nitro drug targets and examine inhibitor activity in vitro and in vivo. In the end, we aim to have validated novel drug targets and developed new inhibitors against these targets as candidates for effective treatment of Mz resistant trichomoniasis. The proposed research will also pave the way for using the same approach to identify and validate new antimicrobials to treat other anaerobic parasitic infections, such as giardiasis and amoebiasis, for which Mz is the primary drug used for therapy.

描述（由适用提供）：单细胞寄生虫Trichomonas阴道负责全世界最普遍，最非病毒，性传播感染，每年约有1/4亿人患有毛son病。 trichomoniasis是美国最常见的寄生虫感染，估计为500万例病例。感染的频率和阴道t. t. t. t. t. t. t. t. t. the的临床分离株数量的增加强调了开发新的化学治疗策略和消除寄生虫的药物。对唯一获得治疗许可的药物，5-硝基咪唑（5NI）药物甲硝唑（MZ）和替替唑（TZ）的耐药性发生在大约5％的trichomoniasis病例中。 5NI是通过厌氧微生物内选择性降低激活的前药，这对于杀死至关重要，但在微生物时也负责抗药性失去了减少5NI的能力。激活后，5NIS通过与基本靶标分子形成共价，灭活的加合物来杀死细胞，这些加合物的定义很差。此处提出的研究的长期目标是定义5NI药物的微生物靶标，这些靶标对于阴道的生存至关重要，并利用该信息来开发有效治疗耐药trichomoniasis的蛋白质靶标的抑制剂。拟议的研究具有五个具体目标。前两个目标将在R21阶段和R33阶段的后三个目标中实现。在AIM 1中，我们将使用采用点击化学和质谱法的策略来确定阴道T.模型菌株中的硝基药物靶标。在AIM 2中，我们将确定哪些蛋白质靶标对于使用反向遗传学来测试消除基因是否致命的阴道生存力至关重要。在过渡到R33阶段后，在AIM 3中，我们将确定硝基药物靶标，这些药物在地理和遗传上多种多样的阴道猪笼草临床分离株中是常见的。在AIM 4中，我们将确定AIM 3中确定的选定的共同目标是否是寄生虫生存能力所必需的。在AIM 5中，我们将开发最有希望的硝基药物靶标和检查抑制剂活性的抑制剂体内。最后，我们的目标是验证新的药物靶标，并开发出针对这些靶标的新抑制剂，作为有效治疗MZ抗MZ型trichomoniasis的候选者。拟议的研究还将为使用相同方法鉴定和验证新的抗菌剂治疗其他厌氧寄生虫感染的新方法铺平道路，例如贾第鞭毛疾病和半oebiasis，MZ是用于治疗的主要药物。