Effects of azithromycin on P. aeruginosa gene expression

阿奇霉素对铜绿假单胞菌基因表达的影响

• 批准号: 6883232
• 负责人: Jane L. Burns
• 金额: $ 7.75万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6883232
• 关键词: Pseudomonas aeruginosa; azithromycin; clinical research; cystic fibrosis; gene expression; gene expression profiling; genetic regulation; human subject; microarray technology; pathologic process; polymerase chain reaction; virulence

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is a genetic disease characterized by airway infection and inflammation with early death resulting from chronic airway disease. Pseudomonas aeruginosa is the most important pathogen in CF airway infections and anti-pseudomonal antibiotics have long demonstrated efficacy in decreasing morbidity and mortality in CF. However, other antibiotics--such as azithromycin--that do not have classical in vitro antimicrobial activity against P. aeruginosa have demonstrated clinical efficacy. A recent clinical trial of azithromycin in the US (for which my laboratory performed quantitative microbiology) demonstrated improvement in lung function and decreased rate of pulmonary exacerbation in those patients who received azithromycin (N = 87) compared with those who received placebo (N = 98), in the absence of a quantitative anti-pseudomonal effect. The mechanism of this activity is not understood, but may be caused by host effects, antibacterial effects or a combination of the two. I have subsequently examined study isolates for an antibiofilm effect and demonstrated no correlation with clinical response. Thus, I hypothesize that azithromycin affects gene expression in P. aeruginosa, which may result in decreased inflammation and improved lung function. Three aims are proposed to test that hypothesis. The first of these is to use gene expression arrays to identify genes in strain PAO1 that are regulated by growth in sub-MIC concentrations of azithromycin. Subsequently, the patient isolates from the US trial of azithromycin in CF will be used to determine whether clinical response to the drug correlates with the presence of azithromycin-regulated genes. Finally, differences in gene regulation between those isolates from responders and non-responders will be examined. The data will be analyzed to determine whether there are specific azithromycin-regulated genes whose expression, or lack of it, is correlated with the CF response to azithromycin therapy. It is hoped that elucidation of this mechanism of action may result in other novel therapies. Additionally, specific markers may be identified to predict CF patient response to azithromycin, thus preventing ongoing treatment with ineffective therapy.

描述（申请人提供）：囊性纤维化（CF）是一种以气道感染和炎症为特征的遗传性疾病，由慢性气道疾病导致早期死亡。铜绿假单胞菌是 CF 气道感染中最重要的病原体，长期以来，抗假单胞菌抗生素已被证明可有效降低 CF 的发病率和死亡率。然而，其他抗生素（例如阿奇霉素）对铜绿假单胞菌不具有经典的体外抗菌活性，但已证明具有临床疗效。最近在美国进行的一项阿奇霉素临床试验（我的实验室对此进行了定量微生物学研究）表明，与接受安慰剂的患者 (N = 98) 相比，接受阿奇霉素治疗的患者 (N = 87) 的肺功能有所改善，肺部病情加重率有所降低。 ），在没有定量抗假单胞菌作用的情况下。这种活性的机制尚不清楚，但可能是由宿主效应、抗菌效应或两者的组合引起的。我随后检查了研究分离株的抗生物膜作用，并证明与临床反应没有相关性。因此，我推测阿奇霉素会影响铜绿假单胞菌的基因表达，这可能会减少炎症并改善肺功能。提出了三个目标来检验该假设。第一个是使用基因表达阵列来鉴定 PAO1 菌株中受亚 MIC 浓度阿奇霉素生长调节的基因。随后，美国阿奇霉素治疗 CF 试验中分离的患者将用于确定该药物的临床反应是否与阿奇霉素调节基因的存在相关。最后，将检查来自应答者和非应答者的分离株之间的基因调控差异。将分析数据以确定是否存在特定的阿奇霉素调节基因，其表达或缺乏与 CF 对阿奇霉素治疗的反应相关。希望阐明这种作用机制可能会产生其他新疗法。此外，可以鉴定特定标记来预测CF患者对阿奇霉素的反应，从而防止正在进行的治疗无效。