Next-generation 5-nitro heterocyclic antimicrobials against mucosal protists

 描述（由申请人提供）：5-硝基药物甲硝唑（Mz）几十年来一直是抗菌治疗的支柱。它的几种简单衍生物，如替硝唑联合收割机结合了类似的活性特征和改进的药代动力学特性，但对现有硝基药物的耐药性正在增加。虽然这类药物的商业开发在几十年前就基本停止了，但我们和其他人在过去几年的工作表明，与现有药物相比，对基本5-硝基杂环的广泛修饰可以显著增强对不同微生物的活性。这些数据表明，Mz和其他批准的硝基药物在这类药物中不具有最佳活性，但必须解决关于新型硝基化合物的潜在效用的重要问题，以促进其作为下一代硝基药物用于临床用途：是否有可能开发具有广谱活性的改进的硝基药物，或者增强的活性仅以微生物特异性方式存在？新的硝基药物是否有不同的靶点，可以用来克服现有药物的耐药性？新型硝基药物的最佳药代动力学特性是什么，以获得对不同靶微生物感染的最大疗效和效力？与现有药物相比，新的硝基药物能否以改进的给药方案开发？这些问题的答案不仅对评估新硝基药物的治疗潜力至关重要，而且对确定特定适应症的新线索也至关重要。该项目将解决这些问题，重点是两个重要的原生动物病原体，阴道毛滴虫和贾第鞭毛虫。我们将评估一个新合成的约1,200种硝基药物库对靶原生动物的广泛药物敏感和耐药菌株的活性，以鉴定比Mz更有效的库化合物。电化学方法将用于确定最有效的硝基化合物的氧化还原性质，以获得有关其作用机制和潜在毒性的新的基本线索。随后，我们将在顶级电极导线中引入新的结构修饰，并评价其生物活性、细胞毒性、电化学特性和产生新耐药性的倾向。最后，我们将评估最有前途的硝基化合物的疗效，效力和药物动力学在不同的原生动物感染的小鼠模型。在完成拟议的研究后，我们希望阐明广泛适用的原则，指导下一代硝基杂环药物在治疗临床上重要的寄生虫病滴虫病和贾第虫病中的最佳疗效。生成的全面数据集也将有助于选择最有希望的候选药物作为改善这些感染治疗的新线索，以及其他重要病原体的潜在感染，包括溶组织内阿米巴、克氏锥虫、幽门螺杆菌和艰难梭菌，可以用硝基抗菌药物治疗。

 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.