Discovery of Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries

使用 DNA 编码化学文库发现碳青霉烯酶抑制剂

基本信息

批准号：
10078242
负责人：
Timothy Palzkill
金额：
$ 60.43万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-18 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078242
关键词：
Active Sites Address Affinity Ampicillin Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Area Bacteria Bacterial Drug Resistance Bacterial Infections Bar Codes Carbapenems Cephalosporins Characteristics Chemicals Clavulanic Acids Clinic Clinical Collection Complex DNA Drug resistance Enterobacteriaceae Enzyme Inhibitor Drugs Enzymes Escherichia coli Future Goals Gram-Negative Bacteria Hospitals Hydrolysis Infection Libraries Medicine Methods Monobactams Multi-Drug Resistance Names Penicillins Pharmaceutical Chemistry Pharmaceutical Preparations Plasmids Production Public Health Rod Roentgen Rays Serine Source Structure Structure-Activity Relationship Technology Work antimicrobial drug bacterial resistance base beta-Lactam Resistance beta-Lactamase beta-Lactams carbapenem resistance carbapenemase clinically relevant college drug development drug discovery experimental study improved inhibitor/antagonist innovation insight novel pathogen resistance mechanism scaffold small molecule small molecule inhibitor small molecule libraries virtual

项目摘要

Project Summary/Abstract Because of their favorable characteristics, β-lactams make up approximately 60% of antibiotic usage worldwide. Bacterial resistance to β-lactam drugs, however, has been steadily increasing, posing a significant threat to antibiotic therapy. The most common mechanism of resistance is β-lactamase-catalyzed hydrolysis, which renders the antibiotics ineffective. An area of particular concern is multi-drug resistant infections caused by Gram-negative rods; leaving few options for treatment. Carbapenems are a class of β-lactam antibiotics that historically have been less susceptible to the action of β-lactamases and have seen increased usage. A rising number of bacterial infections acquired in hospital settings, however, are caused by carbapenem resistant Enterobactericiae (CRE) pathogens. Enterobacteriaceae frequently become resistant to carbapenem antibiotics by acquiring plasmid-encoded β-lactamases named carbapenemases. The three most frequently encountered carbapenemases in clinics worldwide are KPC-2, NDM-1, and OXA-48. The objective of this application is to utilize DNA-encoded chemical library technology to discover small molecule inhibitors of these enzymes. This approach involves the creation of libraries of drug-like molecules covalently attached to a unique DNA barcode that enables identification of binders for a target in a large pool of compounds. DNA-encoded chemical libraries have been constructed at the Center for Drug Discovery at Baylor College of Medicine that encode over 2 billion compounds, allowing a screen of wide chemical space for novel, non-β-lactam inhibitors of these important drug-resistance enzymes. In preliminary studies, we demonstrated the feasibility of the approach by using a DNA-encoded chemical library to identify CDD-97, which inhibits OXA-48 with a Ki of 600 nM. The X-ray structure of OXA-48 in complex with CDD-97 revealed it makes key interactions with active site residues and medicinal chemistry studies have defined structure-activity relationships for the molecule. DNA-encoded chemical library screens will be extended for the OXA-48, NDM-1 and KPC-2 β-lactamases and identified inhibitors will be characterized with respect to potency of inhibition, X-ray structure, spectrum of inhibition, and bioactivity versus bacteria. In addition, medicinal chemistry methods will be used to optimize potency and accumulation of inhibitors in bacteria. The proposed experiments have the potential to yield new, non-β-lactam, inhibitors and provide insights into chemical scaffolds that are favorable for interaction with β-lactamases.

项目概要/摘要由于其良好的特性，β-内酰胺类药物约占抗生素用量的 60% 然而，全球范围内细菌对β-内酰胺药物的耐药性一直在稳步增加，构成了一个严重的问题。对抗生素治疗的重大威胁是最常见的耐药机制。 β-内酰胺酶催化的水解，使抗生素无效。令人担忧的是革兰氏阴性杆菌引起的多重耐药感染，几乎没有选择。碳青霉烯类药物是一类β-内酰胺类抗生素，历史上使用较少。对β-内酰胺酶的作用敏感，并且使用量不断增加。然而，在医院环境中获得的细菌感染是由碳青霉烯类耐药性引起的肠杆菌科 (CRE) 病原体经常对碳青霉烯类抗生素产生耐药性。通过获得质粒编码的β-内酰胺酶（称为碳青霉烯酶）来制备抗生素。全世界临床中经常遇到的碳青霉烯酶是 KPC-2、NDM-1 和 OXA-48。该应用程序的目标是利用 DNA 编码化学库技术来发现小的这些酶的分子抑制剂。这种方法涉及创建类药物库。分子共价连接到独特的 DNA 条形码上，从而能够识别结合物已在大量 DNA 编码的化合物库中构建了目标。贝勒医学院药物发现中心编码超过 20 亿种化合物为这些重要的新型非β-内酰胺抑制剂提供了广阔的化学空间在初步研究中，我们证明了该方法的可行性。使用 DNA 编码的化学文库来鉴定 CDD-97，它可以抑制 OXA-48，Ki 为 600 nM。 OXA-48 与 CDD-97 复合物的 X 射线结构揭示了它与活性位点残留和药物化学研究已经定义了结构-活性关系 DNA 编码的化学库筛选将扩展到 OXA-48、NDM-1 和 KPC-2 β-内酰胺酶和已鉴定的抑制剂将根据其效力进行表征抑制、X 射线结构、抑制谱以及对细菌的生物活性。药物化学方法将用于优化抑制剂的效力和积累所提出的实验有可能产生新的非β-内酰胺抑制剂和提供对有利于与 β-内酰胺酶相互作用的化学支架的见解。