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，并且正在成为全球健康危机。 CFR蛋白赋予了一种抗生素耐药性的一种新兴机制，CFR蛋白催化23S细菌RRNA中腺苷2503的碳8的甲基化。令人担忧的是，这种简单的修饰使靶向核糖体的许多类别的抗生素具有抗性的细菌，包括核糖，包括苯二酚，林糖酰胺，黄唑胺，丙唑啉蛋白，胸膜素蛋白A，链霉素A和大脂蛋白Josamycin和spiramycin。此外，耐药性被赋予lineZolid，lineZolid是一种合成反去唑胺素酮，用于由许多革兰氏阳性细菌引起的感染，包括抗性霉素的肠球菌，耐甲氧西林抗甲基甲基蛋白抗甲基甲基蛋白的葡萄球菌，抗甲基甲基葡萄球菌，以及抗细菌蛋白 - 抗药性链球菌链球菌，以及某些GRAMIA，以及某些GRAMIA，以及某些GRAM-NE。 CFR使用独特的自由基依赖性机制来催化其靶标的甲基化，使用S-腺苷甲氨酸（SAM）作为附加的甲基碳的来源，也是反应中的自由基引发剂。与所有其他相关的酶不同，它所居住的酶家族的其他成员被称为激进的SAM超家族，使用[4FE-4S]的独特铁离子作为SAM的主要结合决定性。本文所述的工作着重于生成CFR的抑制剂，这些抑制剂是为了利用这种新颖的结合模式而设计的。策略包括基于结构的设计，通过计算对接以及高吞吐量方法来告知。希望这些最初的努力将构成一旦这些酶进行验证，这些策略得到了更全面的措施。显然，需要立即采取行动，以防止能够削弱世界上临床相关抗生素的抗药性机制的进一步传播。