Next-generation 5-nitro heterocyclic antimicrobials against mucosal protists

针对粘膜原生生物的下一代 5-硝基杂环抗菌剂

• 批准号: 8962082
• 负责人: LARS ECKMANN
• 金额: $ 63.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-20 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962082
• 关键词: Action Potentials; Address; Cells; Characteristics; Clinical; Clostridium difficile; Complement; Data; Data Set; Development; Dose; Drug Kinetics; Drug resistance; Drug-sensitive; Entamoeba histolytica; Evaluation; Genital system; Giardia lamblia; Giardiasis; Helicobacter pylori; Human; Infection; Intestines; Lead; Libraries; Life; Metronidazole; Microbe; Modeling; Modification; Mus; Nitro Compounds; Oxidation-Reduction; Parasites; Parasitic Diseases; Pharmaceutical Preparations; Prodrugs; Property; Protozoa; Protozoan Infections; Reaction; Regimen; Research; Resistance; Resistance development; Safety; Structure-Activity Relationship; Surface; Testing; Therapeutic; Tinidazole; Toxic effect; Trichomonas Infections; Trichomonas vaginalis; Trypanosoma cruzi; Work; antimicrobial; antimicrobial drug; cytotoxicity; density; design; drug candidate; drug development; improved; in vitro activity; in vivo; insight; microbial; next generation; novel; pathogen; public health relevance; research study; resistant strain

 DESCRIPTION (provided by applicant): The 5-nitro drug, metronidazole (Mz), has been a mainstay of antimicrobial therapy for decades. Several of its simple derivatives such as tinidazole combine similar activity profiles with improved pharmacokinetic properties, but resistance to existing nitro drugs is increasing. Although commercial development of this drug class largely ceased decades ago, work by us and others over the last several years has shown that extensive modifications of the basic 5-nitroheterocyclic ring can lead to marked enhancement in activity against different microbes compared to existing drugs. These data suggest that Mz and other approved nitro drugs do not possess optimal activity in this drug class, yet important questions about the potential utility of novel nitro compounds must be addressed to advance their development as next-generation nitro drugs for clinical use: Is it possible to develop improved nitro drugs with broad-spectrum activity, or do enhanced activities exist only in microbe-specific fashion? Do new nitro drugs have different targets that can be exploited for overcoming resistance to existing drugs? What are the optimal pharmacokinetic properties of novel nitro drugs for maximal efficacy and potency against infections with different target microbes? Can new nitro drugs be developed with improved dosing regimens compared to existing drugs? Answers to these questions are not only critical for assessing the therapeutic potential of new nitro drugs, but are also key for identifying new leads for specific indications. The project will address these questions with a focus on two important protozoan pathogens, Trichomonas vaginalis and Giardia lamblia. We will evaluate a newly synthesized library of ~1,200 nitro drugs for activity against a broad range of drug-sensitive and drug-resistant strains of the target protozoa to identify library compounds more potent than Mz. Electrochemical approaches will be employed for determining the redox properties of the most potent nitro compounds to gain new fundamental clues about their mechanisms of action and potential toxicity. Subsequently, we will introduce new structural modifications into the top leads and evaluate them for bioactivity, cytotoxicity, electrochemical characteristics, and propensity to develop new drug resistance. Finally, we will evaluate the most promising nitro compounds for efficacy, potency, and pharmacokinetics in different murine models of protozoal infections. Upon completion of the proposed research, we expect to have elucidated broadly applicable principles that govern optimal efficacy of next-generation nitro-heterocyclic agents in the treatment of the clinically important parasitic diseases trichomoniasis and giardiasis. The comprehensive data sets to be generated will also be instrumental in selecting the most promising candidates as novel leads for the improved treatment of these infections, and potentially infections with other important pathogens, including Entamoeba histolytica, Trypanosoma cruzi, Helicobacter pylori, and Clostridium difficile, which can be treated with nitro antimicrobials.

 描述（由应用提供）：数十年来，5-硝基药物甲硝唑（MZ）一直是抗菌治疗的中流型。它的几种简单衍生物（例如替替唑）将相似的活性曲线与改善的药代动力学特性相结合，但对现有硝基药物的耐药性正在增加。尽管该药物类别的商业发展几十年前主要停止，但在过去的几年中，我们和其他人的工作表明，与现有药物相比，对基本的5-硝基粒环环的广泛修改可能会导致针对不同微生物的活性显着增强。这些数据表明，在该药物类别中，MZ和其他批准的硝基药物没有潜在的最佳活性，但必须解决有关新型硝基化合物的潜在实用性的重要问题，以提高其发展，因为下一代硝基药物用于临床用途：是否有可能开发具有更高的硝基药物，或者仅在Microbe Pentercect中使用Microbe Packectrum活动，或者在Microbe Penterceptience中创造了良好的活性？新硝基药物是否具有不同的靶标，可以克服对现有药物的抗性？新型硝基药物的最佳药代动力学特性是什么，可最大程度地影响不同的靶标微生物感染？与现有药物相比，可以通过改进的给药方案开发新的硝基药物吗？这些问题的答案不仅对于评估新硝基药物的治疗潜力至关重要，而且还是确定特定指征的新潜在客户的关键。该项目将重点介绍两种重要的原生动物病原体，trichomonas vaginalis和giardia lamblia。我们将评估一个〜1,200硝基药物的新合成的库，用于对靶标原生动物的广泛药物敏感和抗药性菌株的活性，以鉴定库化合物比MZ具有更多的潜力。将采用电化学方法来确定最潜在的硝基化合物的氧化还原特性，以获得有关其作用机理和潜在毒性的新基本线索。随后，我们将向顶级铅中引入新的结构修饰，并评估它们的生物活性，细胞毒性，电化学特征以及发展新药耐药性。最后，我们将评估最有前途的硝基。在原生动物感染的不同鼠模型中，具有效率，效力和药代动力学的化合物。拟议的研究完成后，我们预计将阐明广泛适用的原则，这些原则控制着下一代硝基杂环剂的最佳效率，以治疗临床上重要的寄生疾病会导致三核病症和贾第鞭毛疾病。要生成的综合数据集也将有助于选择最有希望的候选者，作为改善这些感染的新领导，并可能对其他重要病原体感染，包括其他重要病原体，包括溶解性的组织，克鲁氏锥虫锥虫菌，幽门螺杆菌，幽门螺杆菌和梭子杆菌，并与Nitro andro androtrimic进行治疗。