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Evolution and inhibition of beta-lactamase activity in antibiotic resistance

抗生素耐药性中β-内酰胺酶活性的进化和抑制

基本信息

批准号：
9307683
负责人：
Yu Chen
金额：
$ 37.34万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307683
关键词：
Active Sites Affect Affinity Anabolism Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Bacterial Infections Binding Biochemical Biological Models Carbapenems Catalysis Cefotaxime Ceftazidime Cell Wall Cephalosporins Chemicals Clinical Collaborations Cyclophosphamide Development Engineering Enzymes Escherichia coli Evolution Goals Gram-Negative Bacteria Health Hydrolysis In Vitro Investments Lactamase Lactams Lead Ligand Binding Ligands Monobactams Movement Multi-Drug Resistance Mutagenesis Mutation Penicillin-Binding Proteins Penicillins Pharmaceutical Chemistry Pharmaceutical Preparations Positioning Attribute Predisposition Production Property Proteins Protons Research Personnel Resistance Resolution Resort Resources Sampling Serine Site-Directed Mutagenesis Structure Synthesis Chemistry Temperature Testing University Hospitals X ray diffraction analysis X-Ray Crystallography X-Ray Diffraction analog bacterial resistance base beta-Lactamase chemotherapeutic agent clinically relevant design drug discovery enzyme mechanism experimental study inhibitor/antagonist insight lead series mutant novel pathogen pressure protonation prototype public health relevance resistance mechanism resistance mutation suicide substrates

项目摘要

DESCRIPTION (provided by applicant): The production of serine �-lactamase is one of the primary resistance mechanisms used by Gram-negative bacterial pathogens against �-lactam antibiotics, which include the widely used penicillins and cephalosporins, as well as last resort antibiotics such as the carbapenems. The development of novel �-lactamase inhibitors is a pressing need underscored by the continuing mutation of �-lactamases. We propose the development of high affinity non-covalent �-lactamase inhibitors by targeting conserved structural motifs, particularly those essential for extended spectrum �-lactamase activity. Prototypes of these inhibitors have already been identified. Specifically, using the CTX-M Class A �-lactamases as a model system, we aim to: 1) apply a fragment-based and structure-guided approach to develop novel �-lactamase inhibitor chemotypes; 2) study resistance and ligand binding by ultrahigh-resolution and room-temperature X-ray crystallography; and 3) investigate the evolution of resistance mutations against non-covalent inhibitors. These experiments will lead to new �- lactamase inhibitors with clinical potential, while providing a deeper understanding of �-lactamase mutations relevant to resistance evolution.

描述（由申请人提供）：丝氨酸-内酰胺酶的产生是革兰氏阴性细菌病原体对-内酰胺类抗生素的主要耐药机制之一，其中包括广泛使用的青霉素类和头孢菌素类抗生素，以及碳青霉烯类抗生素等最后手段。新型内酰胺酶抑制剂的开发是迫切需要强调的-内酰胺酶的持续突变。我们建议开发高亲和力的非共价内酰胺酶抑制剂，通过靶向保守的结构基序，特别是那些扩展谱内酰胺酶活性所必需的结构基序。这些抑制剂的原型已经被确定。具体而言，以CTX-M A类内酰胺酶为模型系统，我们的目标是：1)应用基于片段和结构引导的方法开发新的内酰胺酶抑制剂化学型；2)利用超高分辨率和室温x射线晶体学研究耐药性和配体结合；3)研究非共价抑制剂耐药突变的进化。这些实验将产生具有临床潜力的新型内酰胺酶抑制剂，同时提供对内酰胺酶突变与耐药性进化相关的更深入了解。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanisms of proton relay and product release by Class A β-lactamase at ultrahigh resolution.

DOI：
10.1111/febs.14315
发表时间：
2018-01
期刊：
The FEBS journal
影响因子：
0
作者：
Lewandowski EM;Lethbridge KG;Sanishvili R;Skiba J;Kowalski K;Chen Y
通讯作者：
Chen Y

Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M β-Lactamase.

DOI：
10.1021/acs.organomet.6b00888
发表时间：
2017-05-08
期刊：
Organometallics
影响因子：
2.8
作者：
Lewandowski EM;Szczupak Ł;Wong S;Skiba J;Guśpiel A;Solecka J;Vrček V;Kowalski K;Chen Y
通讯作者：
Chen Y

Structural Basis and Binding Kinetics of Vaborbactam in Class A β-Lactamase Inhibition.

A 类 β-内酰胺酶抑制中 Vaborbactam 的结构基础和结合动力学。