Next-generation 5-nitro heterocyclic antimicrobials against mucosal protists

 描述(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中流砥柱。它的几个简单的衍生物，如替硝唑，结合了类似的活性曲线和改善的药代动力学特性，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，对碱性5-硝基杂环的广泛修饰可以导致对不同微生物的活性显著增强。这些数据表明，Mz和其他批准的硝基药物在这一类药物中并不具有最佳活性，但必须解决有关新型硝基化合物潜在用途的重要问题，以推动它们作为临床使用的下一代硝基药物的开发：是否有可能开发具有广谱活性的改进硝基药物，或者增强的活性仅存在于微生物特有的方式？新的硝基药物是否有不同的靶点可以用来克服对现有药物的耐药性？对于不同目标微生物的感染，新型硝基药物的最佳药代动力学特性是什么？与现有药物相比，能否通过改进给药方案来开发新的硝基药物？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，而且对于确定特定适应症的新线索也是关键。该项目将解决这些问题，重点关注两种重要的原生动物病原体--阴道毛滴虫和蓝氏贾第鞭毛虫。我们将评估新合成的约1,200种硝基药物对目标原生动物广泛的药物敏感和耐药菌株的活性，以确定比Mz更有效的库化合物。电化学方法将被用来确定最有效的硝基化合物的氧化还原性质，以获得关于它们的作用机制和潜在毒性的新的基本线索。随后，我们将在顶级引线中引入新的结构修饰，并对它们的生物活性、细胞毒性、电化学性质和产生新耐药性的倾向进行评估。最后，我们将评估最有希望的硝基化合物在不同原虫感染小鼠模型中的有效性、效力和药代动力学。在拟议的研究完成后，我们希望阐明广泛适用的原则，这些原则指导下一代硝基杂环药物治疗临床上重要的寄生虫病滴虫病和贾第鞭毛虫病的最佳疗效。将生成的全面数据集还将有助于选择最有希望的候选对象作为改进这些感染以及其他重要病原体的潜在感染治疗的新线索，包括可以用硝基抗菌剂治疗的组织溶解内阿米巴、克氏锥虫、幽门螺杆菌和艰难梭菌。

 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.