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.

项目摘要 致病细菌中的多药耐药性（MDR）具有严重的公共卫生问题。 以前，我们发现头孢辛蛋白可以使耐甲氧西林的金黄色葡萄球菌（MRSA）呈现 再次对奥沙西林敏感。因此，我们假设小分子可能会增加 β-内酰胺对革兰氏+病原体的杀菌活性。筛选约60,000个小型 分子库，我们获得了具有Sub-MIC的MRSA活性的候选化合物 奥沙西林。而复合DNAC-2之一具有广泛的活性和低水平 毒性，其核心结构与5-羟基奎诺林具有相似性，已知有抗细菌 活动。为了开发新颖的衍生物，我们综合了一系列独特的类似物 称为DNAC-23A。与奥沙西林结合使用，DNAC-23A导致奥沙西林降低64倍 MRSA菌株USA300的MIC，为MSSA表型提供MRSA。我们建议 进一步表征DNAC-23A的以下两个具体目的：i）确定 DNAC-23A; ii）进行DNAC-23A的结构活动关系研究。目标 这些研究旨在确定具有提高效率，提高溶解度和的新型衍生物 最小的毒性。未来的研究将侧重于这些化合物的最佳PK/PD值， 因此，使我们能够确定未来药物开发的“铅化合物”。作为治疗 抗性革兰氏+病原体的选项有限，发现延伸的新型化合物 当前β-内酰胺的使用代表了药物开发的潜在进步。