Emergence of TonB-dependent receptor mediated cefiderocol resistance among multidrug-resistant (MDR) Pseudomonas aeruginosa clinical isolates.

多重耐药 (MDR) 铜绿假单胞菌临床分离株中 TonB 依赖性受体介导的头孢地罗耐药性的出现。

• 批准号: 10646641
• 负责人: William R Miller
• 金额: $ 17.17万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646641
• 关键词: Active Biological Transport; Affect; Antibiotic Resistance; Antibiotics; Bacteria; Binding; Biological; Biological Assay; Blood; Carbapenems; Caring; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Clinical; Clinical Data; Clinical Microbiology; Cohort Studies; Collection; Data; Detection; Development; Diameter; Diffusion; Dose; Drug Exposure; Drug Kinetics; Endothelium; Evaluation; Exposure to; Fiber; Gene Mutation; Genetic Polymorphism; Genomics; Geographic Locations; Geography; Goals; Growth; Healthcare; Hospital Referrals; Human; Infection; Integral Membrane Protein; Intensive Care Units; Intermediate resistance; International; Iron; Label; Laboratories; Link; Liquid substance; Lung; Mediating; Medical; Membrane; Methods; Minimum Inhibitory Concentration measurement; Modeling; Multi-Drug Resistance; Mutation; Nonsense Codon; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Population Analysis; Predisposition; Prevalence; Proteins; Pseudomonas; Pseudomonas aeruginosa; Receptor Gene; Regimen; Regulation; Regulatory Pathway; Reporting; Resistance; Risk; Route; Series; Siderophores; Site; Source; Stream; System; Test Result; Testing; Therapeutic Uses; Toxic effect; Treatment Failure; Variant; assay development; beta-Lactamase; beta-Lactams; carbapenem resistance; clinical development; clinical practice; clinically relevant; genome analysis; genome sequencing; healthcare-associated infections; in vitro activity; inhibitor; insertion/deletion mutation; medical vulnerability; multi-drug resistant pathogen; multidrug-resistant Pseudomonas aeruginosa; mutant; novel; pathogen; periplasm; prevent; prospective; protein function; public health emergency; receptor; resistance mechanism; screening; tool; uptake; whole genome

Project Summary The rise of antibiotic resistance among healthcare associated pathogens has created a public health emergency and is a major challenge to the provision of effective medical care. Multidrug-resistant (MDR) Pseudomonas aeruginosa is labeled as a serious threat by the Centers for Disease Control and Prevention, and disproportionately impacts medically vulnerable patients such as those in the intensive care unit. The emergence of resistance to front-line antibiotics, including carbapenems and recently introduced β-lactam/β- lactamase inhibitor combinations, has led to the use of alternate regimens with decreased efficacy and increased toxicity. Cefiderocol (FDC) is a novel siderophore cephalosporin that retains in vitro activity against MDR-P. aeruginosa. This antibiotic mimics the iron binding molecules P. aeruginosa requires for growth, and is actively transported into the periplasmic space by proteins on the outer membrane of the bacteria called TonB dependent receptors (TBDR). Resistance to FDC has been linked to a loss of expression of these TBDRs in clinical isolates of P. aeruginosa. Further, an analysis of genomes of P. aeruginosa collected before the approval of FDC found that mutations predicted to lead to decreased expression of TBDR genes were present in carbapenem-resistant isolates. Using population analysis profiles (PAP), several strains of P. aeruginosa with TBDR mutations showed heteroresistance to FDC, or growth of a small population of bacteria at antibiotic concentrations above the clinical resistance breakpoint despite testing susceptible on standard susceptibility testing. In two major specific aims, this proposal will investigate the hypothesis that mutations in TBDR genes are present across clinical isolates of P. aeruginosa from diverse geographic areas and lead to the emergence of resistance on exposure to FDC. In the first aim, the prevalence of TBDR gene mutations will be evaluated in a collection of nearly one thousand carbapenem-resistant P. aeruginosa from the Prospective Observational Pseudomonas study (POP). Alterations in this pathway will be linked to FDC susceptibility testing results, an assessment of heteroresistance using PAP, and clinical features of P. aeruginosa colonization and infection. In the second aim, we will investigate strategies to understand and mitigate the emergence of resistance associated with TBDR mutations. First, a disk diffusion-based method to identify heteroresistant isolates will be developed as a screening test for the clinical microbiology laboratory. Second, a hollow fiber infection model simulating human pharmacokinetics of FDC will be used to evaluate the emergence of FDC resistance at clinically relevant drug concentrations. This proposal will provide important information on the distribution and prevalence of mutations associated with resistance to FDC in P. aeruginosa. The development of an assay to identify isolates at risk of resistance, and an understanding of the mechanism by which resistance emerges at human drug exposures, can form the basis for rational therapeutic use of FDC at the patient bedside.

项目概要 医疗保健相关病原体中抗生素耐药性的上升造成了公共卫生问题 紧急情况，是提供有效的耐多药（MDR）医疗服务的重大挑战。 铜绿假单胞菌被疾病控制和预防中心标记为严重威胁， 并对医疗上脆弱的患者（例如重症监护病房的患者）产生不成比例的影响。 对一线抗生素（包括碳青霉烯类和最近引入的 β-内酰胺/β-）出现耐药性 内酰胺酶抑制剂组合，导致使用替代疗法，但疗效降低，并且 头孢菌素 (FDC) 是一种新型铁载体头孢菌素，保留了体外抗病毒活性。 MDR-P. 铜绿假单胞菌模仿铜绿假单胞菌生长所需的铁结合分子。 通过细菌外膜上称为 TonB 的蛋白质主动转运至周质空间 依赖性受体 (TBDR) 对 FDC 的耐药性与这些 TBDR 的表达缺失有关。 铜绿假单胞菌的临床分离株进一步，对之前收集的铜绿假单胞菌的基因组进行分析。 FDC 的批准发现存在预计会导致 TBDR 基因表达降低的突变 使用群体分析谱 (PAP)，发现了几种铜绿假单胞菌菌株。 具有 TBDR 突变的细菌对 FDC 表现出异质抗性，或者少数细菌在抗生素作用下生长 尽管按照标准药敏试验进行药敏试验，但浓度仍高于临床耐药性断点 在两个主要具体目标中，该提案将研究 TBDR 基因突变的假设。 存在于来自不同地理区域的铜绿假单胞菌临床分离株中，并导致出现 第一个目标是评估 TBDR 基因突变的患病率。 来自前瞻性观察的近千种耐碳青霉烯类铜绿假单胞菌 假单胞菌研究 (POP) 中该途径的改变将与 FDC 药敏试验结果相关联。 使用 PAP 评估异质抗性，以及铜绿假单胞菌定植和感染的临床特征。 第二个目标，我们将研究了解和减轻阻力出现的策略 首先，将采用基于纸片扩散的方法来识别异抗性分离株。 开发作为临床微生物学实验室的筛选测试第二，中空纤维感染模型。 模拟 FDC 的人体药代动力学将用于评估 FDC 耐药性的出现 该提案将提供有关分布和临床相关药物浓度的重要信息。 铜绿假单胞菌中与 FDC 抗性相关的突变的发生率 检测方法的开发。 识别有耐药性风险的菌株，并了解耐药性出现的机制 人体药物暴露量可以为患者床边合理使用 FDC 的治疗奠定基础。