Development of a Novel Class of Antibiotics with Activity Against Gram-Negative and Gram-Positive Pathogens

开发一类具有抗革兰氏阴性和革兰氏阳性病原体活性的新型抗生素

• 批准号: 9258599
• 负责人: Andrew Riley
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-16 至 2020-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258599
• 关键词: Address; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Benchmarking; Biological; Cell Culture Techniques; Cellular Assay; Chemicals; Clinical; Clinical Data; Collection; Data; Development; Drug Kinetics; Enterococcus; Enterococcus faecium; Escherichia coli; Frequencies; Gram-Negative Bacteria; Health; Human; Infection; Klebsiella pneumonia bacterium; Lead; Membrane; Modeling; Modification; Multi-Drug Resistance; Mus; Organism; Outcome; Pharmaceutical Preparations; Property; Quinolones; Research; Resistance; Route; Series; Staphylococcus aureus; Structure-Activity Relationship; System; Testing; Therapeutic; Topoisomerase; Translating; United States; Work; analog; bacterial resistance; base; clinical candidate; design; drug development; effective therapy; in vivo; killings; member; mouse model; multi-drug resistant pathogen; novel; novel drug class; pathogen; pre-clinical; scaffold

Project Summary The threat of multidrug resistant (MDR) bacterial infections has in recent years led to increased efforts in identifying novel antibacterials. These efforts have resulted in the approval of several new drug classes for Gram-positive infections; however due to the additional challenges imposed by the outer membrane found in Gram-negative bacteria, a novel broad-spectrum agent has not been introduced since 1968. Furthermore, the majority of compounds in the Gram-negative drug development pipeline are derivatives of existing antibiotics, which increases the likelihood of cross-resistance with approved treatments. Thus, there exists a critical need to identify novel classes of broad-spectrum antibiotics, particularly those with activity against MDR pathogens. One class of antibacterials is the nybomycins, which are particularly promising due to their impressive activity against wild-type and MDR S. aureus and Enterococci species in both cell culture and animal models of infection. However their use as broad-spectrum agents is limited by their inability to penetrate into Gram- negative bacteria. It is, therefore, the objective of this application to expand the nybomycin spectrum of activity by designing derivatives that possess suitable activity against both Gram-negative and Gram-positive pathogens. This work will build upon preliminary studies that recently identified the first nybomycin analogue with activity against Gram-negative bacteria. In Specific Aim 1, a collection of nybomycin derivatives will be prepared and evaluated for the ability to inhibit their biological target and accumulate in Gram-negative bacteria. The results from these studies will be used to determine how each of these factors contribute to antibacterial activity and guide the synthesis of more active derivatives. The therapeutic potential of these compounds will be determined in Specific Aim 2 by evaluating their tolerability, pharmacokinetic parameters, and in vivo efficacy in mice. The completion of these studies will have a significant impact on human health by providing a series of nybomycin analogues with significant activity against serious MDR Gram-positive and Gram-negative pathogens as well as the preliminary in vivo data to support their development as a novel drug class.

项目摘要 近年来，多药耐药（MDR）细菌感染的威胁已经导致增加了针对MDR的努力。 发现新的抗菌药物这些努力导致了几种新药类别的批准， 革兰氏阳性菌感染;然而，由于在革兰氏阳性菌中发现的外膜所带来的额外挑战， 革兰氏阴性菌，一种新的广谱剂，自1968年以来没有被引入。而且 革兰氏阴性药物开发管道中的大多数化合物是现有抗生素的衍生物， 这增加了与批准的治疗交叉耐药性的可能性。因此，迫切需要 鉴定新型广谱抗生素，特别是对MDR病原体具有活性的抗生素。 一类抗菌药物是尼博霉素，由于其令人印象深刻的活性， 抗野生型和MDR S.金黄色葡萄球菌和肠球菌物种在细胞培养和动物模型， 感染然而，它们作为广谱剂的用途受到它们不能渗透到革兰氏阴性菌中的限制。 阴性细菌。因此，本申请的目的是扩大尼博霉素的活性谱 通过设计对革兰氏阴性菌和革兰氏阳性菌都具有合适活性的衍生物， 病原体这项工作将建立在最近确定的第一个尼博霉素类似物的初步研究的基础上 具有抗革兰氏阴性菌的活性。在具体目标1中，将收集尼博霉素衍生物。 制备并评价其抑制其生物靶标和在革兰氏阴性菌中积累的能力 细菌这些研究的结果将用于确定这些因素中的每一个如何影响 抗菌活性和指导活性更高的衍生物的合成。这些药物的治疗潜力 将在具体目标2中通过评价化合物的耐受性、药代动力学参数 和小鼠体内功效。这些研究的完成将对人类健康产生重大影响， 提供了一系列对严重MDR革兰氏阳性菌具有显著活性的尼波霉素类似物， 革兰氏阴性病原体以及支持其作为新药开发的初步体内数据 课