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

• 批准号: 10311533
• 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
• 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/10311533
• 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; innovation; insight; novel; pathogen; resistance mechanism; scaffold; small molecule; small molecule inhibitor; small molecule libraries; virtual

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.

项目摘要/摘要 由于其良好的特性，β-内酰胺类药物约占抗生素使用的60% 全世界。然而，细菌对β-内酰胺类药物的耐药性一直在稳步增加，造成了 对抗生素治疗的重大威胁。最常见的抗性机制是 β-内酰胺酶催化的水解，使抗生素无效。一个特别的领域 令人担忧的是由革兰氏阴性杆菌引起的多重耐药感染；几乎没有选择 治疗。碳青霉烯类是一类β-内酰胺类抗生素，历史上较少 对β-内酰胺酶的作用敏感，使用量增加。数量不断增加的 然而，在医院环境中获得的细菌感染是由碳青霉烯耐药引起的 肠杆菌属(CRE)病原菌。肠杆菌科细菌经常对碳青霉烯类产生耐药性 通过获得被称为碳青霉烯酶的质粒编码的β内酰胺酶来治疗抗生素。最多的三个 世界各地临床上常见的碳青霉烯酶有KPC-2、NDM-1和OXA-48。这个 这项应用的目的是利用DNA编码的化学库技术来发现小分子 这些酶的分子抑制剂。这种方法包括创建类药物的图书馆 分子共价连接到一种独特的DNA条形码，该条形码能够识别 在一大堆化合物中寻找目标。DNA编码的化学库已在 贝勒医学院的药物发现中心编码了20多亿种化合物， 为筛选这些重要的新型非β-内酰胺类抑制剂提供了广阔的化学空间 耐药酶。在初步研究中，我们通过以下方式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，它抑制OXA-48的Ki为600 nM。 OXA-48与CDD-97络合物的X射线结构表明，它与CDD-97 活性部位残基和药物化学研究已经确定了结构-活性关系 分子。DNA编码的化学库屏幕将扩展到OXA-48、NDM-1和 Kpc-2β-内酰胺酶和已确定的抑制剂将根据其效力进行表征 抑制力、X射线结构、抑制谱和对细菌的生物活性。此外, 将使用药物化学方法来优化抑制剂的效力和积累 细菌。拟议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。