Polymyxin-resistant Pseudomonas in CF Lung Infection

CF 肺部感染中的多粘菌素耐药假单胞菌

• 批准号: 7817031
• 负责人: SAMUEL M MOSKOWITZ
• 金额: $ 68.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7817031
• 关键词: Adult; Alleles; Analytical Chemistry; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Genes; Binding; Breathing; Cell Wall; Cell Wall Alteration; Chronic; Clinical; Clinical Microbiology; Colistin; Collection; Cystic Fibrosis; DNA Sequence; Data; Dependence; Detection; European; Gas-Liquid Chromatography; Genes; Genetic; Goals; Gram-Negative Bacteria; Human; Individual; Infection; Interdisciplinary Study; International; Laboratories; Lipid A; Lung; Mass Spectrum Analysis; Methods; Microbe; Modification; Molecular; Multi-Drug Resistance; Mutagenesis; Mutate; Mutation; Operon; Phenotype; Play; Polymyxin Resistance; Polymyxins; Predisposition; Pseudomonas; Pseudomonas aeruginosa; Public Health; Reproducibility; Research Personnel; Resistance; Resources; Role; Structure; System; Testing; Work; aminoarabinose; antimicrobial; bacterial genetics; base; cystic fibrosis patients; drug development; mutant; novel; pathogen; programs; research study; resistance mechanism; resistant strain; tool

DESCRIPTION (provided by applicant): Project Summary: Serious human infections caused by Pseudomonas aeruginosa and other intrinsically antibiotic-resistant pathogens are frequent occurrences. Clinicians increasingly depend on alternative antibiotics like polymyxin (Pm) to treat such infections. Binding of Pm to lipid A, a component of the bacterial cell wall, is key to its antimicrobial mechanism of action. Recently, highly Pm-resistant (PmR) strains of P. aeruginosa have been cultured from European cystic fibrosis (CF) patients who were failing treatment with inhaled Pm. These strains have modified lipid A. Data show that in the US, ~20% of CF adults with chronic P. aeruginosa airway infection were treated with inhaled Pm during 2003-2005, most of them receiving this treatment routinely. Moreover, ~5% of CF isolates identified in US clinical microbiology labs as multidrug-resistant P. aeruginosa in the past 6 years represent PmR strains. The goal of the proposed interdisciplinary project is to define resistance mechanisms in PmR CF strains of P. aeruginosa as potential targets for drug development. The specific aims of the project are to: (1) optimize the reliability of Pm susceptibility testing for PmR strains of P. aeruginosa; (2) define the dependence of CF strain Pm resistance on specific lipid A structures and PmrAB-regulated genetic loci; and (3) define additional genetic loci required for CF strain Pm resistance. These aims will be accomplished by using the tools of analytical chemistry, mass spectrometry, bacterial genetics, and DNA sequencing to define resistance phenotypes and lipid A structures of an international collection of PmR CF strains, identify novel Pm resistance genes in these strains, and determine the dependence of resistance phenotypes on known and novel Pm resistance genes. Relevance: Because of antibiotic-resistant infections such as those caused by Pseudomonas, doctors are using alternative antibiotics like polymyxin more often. Polymyxin-resistant Pseudomonas has now been found in European cystic fibrosis patients for whom polymyxin treatment was not working, and similar bacteria have been found in cystic fibrosis patients in the US. An interdisciplinary study of polymyxin resistant Pseudomonas from patients with cystic fibrosis is proposed to pinpoint the bacterial genes responsible for this resistance, so that management strategies may be devised to overcome it.

描述（由申请人提供）： 项目概要：由铜绿假单胞菌和其他抗生素固有耐药病原体引起的严重人类感染经常发生。临床医生越来越依赖多粘菌素 (Pm) 等替代抗生素来治疗此类感染。 Pm 与细菌细胞壁成分脂质 A 的结合是其抗菌作用机制的关键。最近，从吸入 Pm 治疗失败的欧洲囊性纤维化 (CF) 患者中培养出高度抗 Pm (PmR) 的铜绿假单胞菌菌株。这些菌株改变了脂质 A。数据显示，在美国，约 20% 患有慢性铜绿假单胞菌气道感染的 CF 成人在 2003 年至 2005 年期间接受了吸入 Pm 治疗，其中大多数人常规接受这种治疗。此外，美国临床微生物学实验室鉴定出约 5% 的 CF 分离株具有多重耐药性 过去6年的铜绿假单胞菌代表PmR菌株。拟议的跨学科项目的目标是确定铜绿假单胞菌 PmR CF 菌株的耐药机制，作为药物开发的潜在目标。该项目的具体目标是：（1）优化铜绿假单胞菌PmR菌株Pm药敏试验的可靠性； (2) 定义CF菌株Pm抗性对特定脂质A结构和PmrAB调节的遗传位点的依赖性； (3) 确定 CF 菌株 Pm 抗性所需的额外遗传位点。这些目标将通过使用分析化学、质谱、细菌遗传学和 DNA 测序等工具来定义国际 PmR CF 菌株的耐药表型和脂质 A 结构，识别这些菌株中新的 Pm 耐药基因，并确定抗性表型对已知和新型 Pm 抗性基因的依赖性。 相关性：由于假单胞菌引起的抗生素耐药性感染，医生更频繁地使用多粘菌素等替代抗生素。目前，在多粘菌素治疗无效的欧洲囊性纤维化患者中发现了多粘菌素耐药性假单胞菌，在美国的囊性纤维化患者中也发现了类似的细菌。建议对囊性纤维化患者的多粘菌素耐药性假单胞菌进行跨学科研究，以查明导致这种耐药性的细菌基因，以便制定管理策略来克服它。

项目成果

Effects of azithromycin in Pseudomonas aeruginosa burn wound infection.

阿奇霉素对铜绿假单胞菌烧伤创面感染的影响。

• DOI: 10.1016/j.jss.2013.02.003
• 发表时间: 2013-08
• 期刊: The Journal of surgical research
• 作者: Nichols, David P.;Caceres, Silvia;Caverly, Lindsay;Fratelli, Cori;Kim, Sun Ho;Malcolm, Ken;Poch, Katie R.;Saavedra, Milene;Solomon, George;Taylor-Cousar, Jennifer;Moskowitz, Samuel;Nick, Jerry A.
• 通讯作者: Nick, Jerry A.