Optimization of a novel compound that enhances the activity of beta-lactams against Gram+ bacteria

增强 β-内酰胺抗革兰氏菌活性的新型化合物的优化

• 批准号: 9296686
• 负责人: Ambrose Lin Yau Cheung
• 金额: $ 21.24万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296686
• 关键词: Affinity Chromatography; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Binding; Binding Proteins; Biological Assay; Cefoxitin; Chemicals; Chemosensitization; Coupled; Daptomycin; Data; Drug resistance; Drug-sensitive; Enterococcus; Exhibits; Future; Genetic; Genomics; Genotype; Goals; Hospitals; Infection; Infection Control; Intellectual Property; Lactams; Lead; Libraries; Linezolid; Mass Spectrum Analysis; Measures; Methicillin Resistance; Minimum Inhibitory Concentration measurement; Modification; Molecular Target; Monobactams; Multi-Drug Resistance; New Agents; Nosocomial Infections; Organism; Oxacillin; Parents; Pharmaceutical Preparations; Phenotype; Plasma; Plasma Proteins; Positioning Attribute; Prevalence; Procedures; Property; Public Health; Reporting; Resistance; Resort; Series; Site; Solubility; Staphylococcus aureus; Staphylococcus epidermidis; Structure; Structure-Activity Relationship; Techniques; Time; Toxic effect; Vancomycin; Work; activity-based protein profiling; analog; antimicrobial; aqueous; bacterial resistance; bactericide; base; beta-Lactamase; beta-Lactams; carbapenemase; crosslink; drug development; improved; inhibitor/antagonist; insertion/deletion mutation; killings; methicillin resistant Staphylococcus aureus; mutant; novel; pathogen; pathogenic bacteria; quinoline; response; screening; small molecule; small molecule libraries

Project Summary Multidrug resistance (MDR) in pathogenic bacteria poses a serious public-health problem. Previously, we have discovered cefoxitin can render methicillin-resistant S. aureus (MRSA) strains sensitive again to oxacillin. We thus hypothesize that small molecules may augment the bactericidal activity of β-lactams against Gram+ pathogens. After screening a ~60,000 small- molecule library, we obtained candidate compounds with activity against MRSA with sub-MIC oxacillin. While one of the compound DNAC-2 has broad-spectrum activity and low level of toxicity, its core structure shares similarity to 5-hydroxy-quinoline, known to have anti-bacterial activity. To develop novel derivatives, we synthesized a series of unique analogs one of which is called DNAC-23a. In combination with oxacillin, DNAC-23a led to a 64-fold decrease in oxacillin MIC of MRSA strain USA300, rendering an MRSA to a MSSA phenotype. We propose to further characterize DNAC-23a with the following two specific aims: I) to identify the target of DNAC-23a; II) to conduct Structure-Activity-Relationship studies of DNAC-23a. The goal of these studies is to identify novel derivatives with improved efficacy, improved solubility and minimal toxicity. Future studies will focus on the optimal PK/PD values of these compounds, thus enabling us to identify a “lead compound” for future drug development. As treatment options for resistant Gram+ pathogens are limited, discovery of novel compounds that extend the usage of current beta-lactams represents a potential advance in drug development.

项目概要 致病菌的多重耐药性（MDR）造成了严重的公共卫生问题。 此前，我们发现头孢西丁可以使金黄色葡萄球菌（MRSA）产生耐药性 菌株对苯唑西林再次敏感。因此，我们假设小分子可能会增强 β-内酰胺对革兰氏+病原体的杀菌活性。在筛选了约 60,000 个小样本后 分子库中，我们获得了具有亚 MIC 抗 MRSA 活性的候选化合物 苯唑西林。其中一种化合物 DNAC-2 具有广谱活性和低水平 毒性，其核心结构与5-羟基喹啉相似，已知具有抗菌作用 活动。为了开发新的衍生物，我们合成了一系列独特的类似物，其中之一是 称为DNAC-23a。 DNAC-23a 与苯唑西林联合使用可使苯唑西林浓度降低 64 倍 MRSA 菌株 USA300 的 MIC，将 MRSA 转化为 MSSA 表型。我们建议 进一步表征 DNAC-23a 具有以下两个具体目标：I) 确定 DNAC-23a 的靶标 DNAC-23a； II) 进行DNAC-23a的结构-活性-关系研究。目标是 这些研究旨在鉴定具有改进功效、改进溶解度和 毒性最小。未来的研究将集中于这些化合物的最佳 PK/PD 值， 从而使我们能够确定未来药物开发的“先导化合物”。作为治疗 抗性革兰氏+病原体的选择是有限的，新化合物的发现可以延长 当前β-内酰胺的使用代表了药物开发的潜在进步。