Chemoenzymatic studies of aminoglycoside-resistance enzymes towards new drugs

新药氨基糖苷类耐药酶的化学酶学研究

基本信息

批准号：
8307324
负责人：
Sylvie Garneau-Tsodikova
金额：
$ 31.58万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307324
关键词：
Acetylation Acetyltransferase Acquired Immunodeficiency Syndrome Acute Acyl Coenzyme A Affinity Amines Aminoglycoside Antibiotics Aminoglycoside resistance Aminoglycosides Anti-Bacterial Agents Antibiotics Bacillus anthracis Bacteria Bacterial Infections Biochemical Biological Chemicals Chemistry Clinic Clinical Coenzyme A Collaborations Complement Complex Cystic Fibrosis Development Disease Drug Delivery Systems Drug resistance Drug resistance in tuberculosis Enterococcus faecalis Enzymes Extreme drug resistant tuberculosis Family Health Homologous Gene Human In Vitro Kanamycin A Kinetics Klebsiella pneumonia bacterium Lead Libraries Malignant Neoplasms Methodology Methods Michigan Modification Multi-Drug Resistance Mycobacterium tuberculosis N acylation One-Step dentin bonding system Parents Pathway interactions Pharmaceutical Preparations Positioning Attribute Proteins Public Health Research Resistance Resistance development Ribosomes Series Solutions Structure Testing Therapeutic Time Toxic effect Tuberculosis Universities Work aminoglycoside acetyltransferase analog antimicrobial drug bacterial resistance chemical synthesis combat cost drug resistant bacteria fascinate improved inhibitor/antagonist innovation insight novel novel therapeutics pathogen pathogenic bacteria prevent resistance mechanism resistant strain therapeutic protein

项目摘要

DESCRIPTION (provided by applicant): Aminoglycosides are broad-spectrum antibiotics used for treatment of serious bacterial infections, including the deadly tuberculosis and those accompanying AIDS, cystic fibrosis, and cancer. The emergence of pathogens resistant to these drugs represents a major threat to public health and underscores the need for new antimicrobial agents. In Aim 1, we propose to utilize aminoglycoside-modifying enzymes of the aminoglycoside acetyltransferase (AAC) family in conjunction with a newly developed 6'-N-acylation protecting group-free chemical methodology (i) to generate in vitro libraries of new and more potent N-acylated aminoglycoside antibiotics, and (ii) to develop aminoglycoside probes that will serve as baits for identification of novel therapeutic protein targets/pathways for these antibiotics. Our chemoenzymatic and chemical strategies offer an effective solution to the following problems: (i) there are no existing general synthetic methodologies for the creation of N-acylated aminoglycosides, and (ii) there are no efficient methods to chemically modify specific amine groups on an aminoglycoside that contains a series of chemically identical amines. A few existing examples that use solely chemical syntheses are too demanding on research time and cost and are limited to very specific cases. In Aim 2, we propose biochemical and structural studies of the mechanism of action and inhibition of a major determinant of aminoglycoside resistance in extensively drug-resistant strains of M. tuberculosis (XDR-TB). We expect this work to (i) advance the basic understanding of AG resistance of a variety of pathogenic bacteria, including M. tuberculosis, and (ii) provide a potential solution to overcome the aminoglycoside resistance problem in majority of XDR- TB. Relevance to public health: We expect that this work will contribute to the development of novel antibiotics with a potential to combat existing and newly emerging drug-resistant bacteria.

描述（由申请人提供）：氨基糖苷类是广谱抗生素，用于治疗严重的细菌感染，包括致命的结核病以及伴随艾滋病、囊性纤维化和癌症的感染。对这些药物产生耐药性的病原体的出现对公众健康构成了重大威胁，并强调了对新抗菌药物的需求。在目标 1 中，我们建议利用氨基糖苷乙酰转移酶 (AAC) 家族的氨基糖苷修饰酶结合新开发的 6'-N-酰化保护基团化学方法 (i) 来生成新的和更多的体外文库。有效的N-酰化氨基糖苷类抗生素，以及（ii）开发氨基糖苷类探针，作为识别这些抗生素的新型治疗蛋白靶点/途径的诱饵。我们的化学酶和化学策略为以下问题提供了有效的解决方案：(i) 没有现有的通用合成方法来创建 N-酰化氨基糖苷，以及 (ii) 没有有效的方法来化学修饰 N-酰化氨基糖苷上的特定胺基团。含有一系列化学性质相同的胺的氨基糖苷。一些仅使用化学合成的现有例子对研究时间和成本要求过高，并且仅限于非常具体的情况。在目标 2 中，我们建议对广泛耐药结核分枝杆菌 (XDR-TB) 菌株中氨基糖苷类耐药的主要决定因素的作用和抑制机制进行生化和结构研究。我们期望这项工作能够（i）增进对包括结核分枝杆菌在内的多种病原菌的 AG 耐药性的基本了解，以及（ii）为克服大多数广泛耐药结核病的氨基糖苷类耐药性问题提供潜在的解决方案。与公共卫生的相关性：我们期望这项工作将有助于新型抗生素的开发，这些抗生素有可能对抗现有和新出现的耐药细菌。