Mechanisms of macrolide resistance in mycobacteria

分枝杆菌大环内酯类耐药机制

• 批准号: 6680530
• 负责人: KEVIN A NASH
• 金额: $ 11.16万
• 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 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6680530
• 关键词: Mycobacterium; azithromycin; bacterial genetics; clarithromycin; drug resistance; macrolide antibiotics; polymerase chain reaction; site directed mutagenesis

DESCRIPTION (provided by applicant): The cornerstones for controlling infections caused by non-tuberculosis mycobacteria (NTM) are the macrolides, clarithromycin and azithromycin. The genetic basis of clinically acquired resistance to these agents is conferred by mutation in the 23S ribosomal RNA (rRNA) gene. However, we understand little of the mechanisms of intrinsic macrolide resistance of mycobacteria, particularly M. tuberculosis. Recent studies suggest that mycobacteria have erm methylase genes and macrolide efflux pumps, which may affect susceptibility to macrolides. Therefore, we hypothesize that there are several mechanisms that affect the antimycobacterial activity of macrolides. These mechanisms include drug efflux, expression of erm genes, and, the acquisition of a 23S rRNA gene mutation. Consequently, the long-term objective of this work is to characterize the mutation-independent mechanisms that affect mycobacterial susceptibility to macrolides. To address this objective, this project is divided in to 3 specific aims: (1) to identify the genes conferring inducible macrolide resistance; (2) to investigate the macrolide efflux systems of mycobacteria; and, (3) to characterize the prevalence of resistance genes within the Mycobacteriaceae. Understanding the processes that affect the antimycobacterial activity of macrolides will directly impact the development of new drugs and improve treatment regimens. Of particular interest is improving the anti-tuberculosis activity of macrolides.

描述（由申请人提供）：用于控制由非链局部分子的分支病（NTM）引起的感染的基石是大环内酯类，克拉霉素和阿奇霉素。在23S核糖体RNA（RRNA）基因中突变赋予了临床获得抗性的遗传基础。但是，我们对分枝杆菌的内在大花环耐药性，尤其是结核分枝杆菌的机制几乎没有理解。最近的研究表明，分枝杆菌具有Erm甲基酶基因和大环内酯类外排泵，这可能会影响对大环内酯类的易感性。因此，我们假设有几种影响大环内酯类抗菌活性的机制。这些机制包括药物外排，ERM基因的表达以及23S rRNA基因突变的获取。因此，这项工作的长期目的是表征影响分枝杆菌对大花环的易感性的非依赖性机制。为了解决这一目标，该项目分为3个特定目的：（1）确定赋予诱导大花生酯抗性的基因； （2）调查分枝杆菌的大环内酯类外排系统； （3）表征分枝杆菌科内抗性基因的流行率。了解影响大环内酯类抗菌活性的过程将直接影响新药的发展并改善治疗方案。特别有趣的是改善大环内酯类的抗结核活性。