Radical strategies for inhibiting the antibiotic resistance protein, Cfr

抑制抗生素耐药蛋白 Cfr 的激进策略

• 批准号: 8684786
• 负责人: SQUIRE J. BOOKER
• 金额: $ 18.02万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684786
• 关键词: Adenosine; Amidines; Antibiotic Resistance; Antibiotics; Binding; Carbon; Complex; Docking; Electrons; Engineering; Enzymes; Epitopes; Escherichia coli; Family member; Genes; Genus staphylococcus; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Guanosine Triphosphate; Health; Housekeeping; Hydrolysis; Infection; Intervention; Ions; Iron; Linezolid; Macrolides; Metals; Methicillin Resistance; Methods; Methylation; Methyltransferase; Modification; Multi-Drug Resistance; Oxazolidinones; Penicillin Resistance; Peptides; Peptidyltransferase; Play; Proteins; Reaction; Research; Resistance; Ribosomal Proteins; Ribosomal RNA; Ribosomes; S-Adenosylmethionine; Series; Site; Source; Streptococcus; Streptogramins; Structure; Vancomycin resistant enterococcus; Work; bacterial resistance; base; carboxylate; clinically relevant; design; global health; inhibitor/antagonist; lincosamide; novel; pathogen; pleuromutilin; prevent; public health relevance; resistance mechanism

DESCRIPTION (provided by applicant): Antibiotic resistance among bacterial pathogens is on the rise, and is becoming a global health crisis. One emerging mechanism of antibiotic resistance is conferred by the Cfr protein, which catalyzes the methylation of carbon 8 of adenosine 2503 in 23S bacterial rRNA. Worryingly, this simple modification renders bacteria resistant to a number of classes of antibiotics currently in use that target the ribosome, includin phenicols, lincosamides, oxazolidinones, pleuromutilins, streptogramin A, and the macrolides josamycin and spiramycin. Moreover, resistance is conferred to linezolid, a synthetic oxazolidinone that is indicated for infections caused by a number of Gram-positive bacteria, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and penicillin-resistant streptococci, as well as some Gram-negative bacteria. Cfr uses a unique, radical-dependent, mechanism to catalyze methylation of its target, using S-adenosylmethionine (SAM) both as the source of the appended methyl carbon and as a radical initiator in the reaction. Unlike all other SAM- dependent enzymes, Cfr and other members of the family of enzymes in which it resides, dubbed the radical SAM superfamily, use a unique iron ion of a [4Fe-4S] as a major binding determinant for SAM. The work described herein focuses on generating inhibitors of Cfr that are engineered to take advantage of this novel binding mode. Strategies include structure-based design that is informed by computational docking as well as high throughput methods. It is hoped that these initial efforts will form the basis of a more comprehensive undertaking once these strategies are validated for this class of enzymes. It is clear that immediate action is required to prevent further spread of a resistance mechanism that has the ability to cripple the world's arsenal of clinically relevant antibiotics.

描述（由申请人提供）：细菌病原体中的抗生素耐药性正在上升，并正在成为全球健康危机。一种新出现的抗生素耐药性机制是由Cfr蛋白赋予的，其催化细菌23 S rRNA中腺苷2503的碳8的甲基化。令人担忧的是，这种简单的修饰使细菌对目前使用的靶向核糖体的许多类抗生素产生耐药性，包括非尼醇类、林可酰胺类、恶唑烷酮类、截短侧耳素、链阳霉素A以及大环内酯类交沙霉素和螺旋霉素。此外，利奈唑胺也具有耐药性，利奈唑胺是一种合成恶唑烷酮，适用于多种革兰氏阳性菌引起的感染，包括万古霉素耐药肠球菌、甲氧西林耐药葡萄球菌和青霉素耐药链球菌以及一些革兰氏阴性菌。CFR使用独特的自由基依赖性机制来催化其靶点的甲基化，使用S-腺苷甲硫氨酸（SAM）作为附加甲基碳的来源和反应中的自由基引发剂。与所有其他SAM依赖性酶不同，Cfr和它所在的酶家族的其他成员（被称为自由基SAM超家族）使用独特的铁离子α [4Fe-4S]作为SAM的主要结合决定簇。本文所述的工作集中于产生Cfr的抑制剂，其被工程化以利用这种新的结合模式。策略包括基于结构的设计，其通过计算对接以及高通量方法来通知。希望这些初步的努力将形成一个更全面的事业一旦这些策略被验证这类酶的基础。很明显，需要立即采取行动，以防止有能力削弱世界上临床相关抗生素库的耐药性机制的进一步传播。