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

基本信息

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
项目类别：
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

项目摘要

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）产生耐药性因此，我们发现小分子可能会增强对苯唑西林的敏感性。筛选了约 60,000 种小分子后，β-内酰胺对革兰氏阳性病原体具有杀菌活性。分子库中，我们获得了具有亚 MIC 抗 MRSA 活性的候选化合物而其中一种化合物 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 DNAC-23a 与苯唑西林联合使用，DNAC-23a 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。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。这些研究旨在鉴定具有改进功效、改进溶解度和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”作为治疗方法。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。