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（由申请人提供）：数十年来，5-硝基药物甲硝唑（MZ）一直是抗菌疗法的中流型。如图所示，基本的5-核心环的广泛修改会导致对现有药物的不同微生物的活性明显增强，这表明MZ和其他认可的硝基药物在此药物类别中没有最佳的活性，但重要的问题关于新硝基化合物的潜在效用，必须以临床用途的下一代硝基药物来提高其发育：是否可以开发具有广谱活动的地毯，或者仅以微生物特异性的方式存在增强活动？新的硝基药物具有不同的靶标，可以克服对现有药物的抗性？贾迪亚·兰布利亚（Giardia Lamblia）。有效的硝基化合物可以获得有关D潜力毒物的机制的新基本线索，我们将向顶级铅引入新的结构修饰，并评估它们的生物效果，以进行生物效果，并具有开发新耐药性或耐药性的倾向。在临床上重要的C疾病的触发下，硝基异环节的视力质量的效力和药代动力学在临床上重要的C疾病中，这些原则的原始原理是硝基 - 异环节的能力。就像这些感染的图像一样，可能会与其他重要病原体（包括Entamoeba Historytica，Helicobacter Lori和艰难梭状芽胞杆菌）的无情，可以用硝基抗微生物治疗。