Mechanisms of Macrolide Resistance in Mycobacteria

分枝杆菌大环内酯类耐药机制

• 批准号: 7538376
• 负责人: KEVIN A NASH
• 金额: $ 27.56万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538376
• 关键词: Address; Adenine; Affect; Alleles; Antimicrobial Effect; Antimycobacterial Agents; Azithromycin; Bacteria; Blast Cell; Chronic; Clarithromycin; Complex; Data; Databases; Development; Disease; Drug Transport; Enzymes; Gene Mutation; Genes; Genus Mycobacterium; Goals; Human; Infection; Investigation; Link; Macrolide-resistance; Macrolides; Membrane; Membrane Protein Gene; Membrane Proteins; Methylation; Molecular; Mutation; Mycobacteriaceae; Mycobacterium tuberculosis; Nature; New Agents; Pharmaceutical Preparations; Post-Translational Regulation; Predisposition; Principal Investigator; Process; Prophylactic treatment; Proteins; Recovery; Resistance; Ribosomal RNA; Ribosomes; Role; Site-Directed Mutagenesis; SmpB protein; Southern Blotting; System; Translations; Treatment Protocols; Work; bactericide; base; clinically significant; design; gene function; mycobacterial; non-tuberculosis mycobacteria; novel; pathogen; polypeptide; programs; protein function; rRNA Genes; rRNA methylase; repository; tool

DESCRIPTION (provided by applicant): The cornerstones of prophylaxis and treatment of infections caused by non-tuberculosis mycobacteria (NTM) are the macrolides, clarithromycin and azithromycin. Although clinically acquired macrolide resistance in mycobacteria is conferred by 23S rRNA gene mutation, intrinsic resistance involves expression of adenine rRNA methylases, or erm genes. Moreover, recent data indicates that other genes can significantly affect the antimycobacterial activity of macrolides. For instance, an rpsA gene allele confers high-level macrolide resistance, and evidence suggests that disruption of trans-translation increases the bactericidal activity of macrolides. In addition, Mycobacteria may have a macrolide efflux system. Therefore, we hypothesize that mycobacteria may have several mechanisms that reduce the antimicrobial effects of macrolides. These mechanisms may include target modification (e.g., rRNA methylation or mutation), target recovery (e.g., trans-translation), and drug transport (e.g., efflux). Consequently, the long-term objective of this work is to characterize the mechanisms that affect the susceptibility of mycobacteria to macrolides. To address this objective, the project is divided into 4 specific aims: (1) to characterize the erm genes of mycobacteria; (2) to correlate the function of the rpsA and smpB genes with resistance to and recovery from the affects of macrolides; (3) to characterize the putative membrane protein genes that affect susceptibility to macrolides; and (4) to define the distribution of genes that affect the activity of macrolides within the Mycobacteriaceae. Mycobacteria are important human pathogens that cause chronic, often intractable disease. Understanding resistance and other processes that reduce drug activity will aid the design and development of new agents with activity against mycobacteria and/or treatment regimens.

描述（由申请人提供）：预防的基石和由非连血性分枝杆菌（NTM）引起的感染的治疗是Macrolides，Clarithromycin和Azithromycin。尽管23S rRNA基因突变赋予了临床上获得的大杆菌抗性，但固有耐药性涉及腺嘌呤RRNA甲基酶或ERM基因的表达。此外，最近的数据表明，其他基因可以显着影响大环内酯类药物的抗菌活性。例如，RPSA基因等位基因赋予高水平的大花环耐药性，证据表明，跨翻译的破坏会增加大环内酯类的杀菌活性。另外，分枝杆菌可能具有大花环外排系统。因此，我们假设分枝杆菌可能具有几种降低大环内酯类抗菌作用的机制。这些机制可能包括目标修饰（例如，rRNA甲基化或突变），靶恢复（例如，翻译）和药物转运（例如，外排）。因此，这项工作的长期目的是表征影响分枝杆菌对大环内酯类药物的敏感性的机制。为了解决这一目标，该项目分为4个特定目的：（1）表征分枝杆菌的ERM基因； （2）将RPSA和SMPB基因的功能与对大环内酯类影响的耐药性和恢复相关联； （3）表征影响对大花环易感性的假定膜蛋白基因； （4）定义影响分枝杆菌科中大环内酯类活性的基因的分布。 分枝杆菌是引起慢性疾病的重要人类病原体。了解耐药性和其他减少药物活性的过程将有助于使用针对分枝杆菌和/或治疗方案的活性的新药物的设计和开发。