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.

项目摘要 医疗保健相关病原体中抗生素耐药性的上升已经创造了一个公共卫生 这是一种紧急情况，是提供有效医疗保健的一项重大挑战。耐多药(MDR) 铜绿假单胞菌被疾病控制和预防中心列为严重威胁， 并不成比例地影响医疗脆弱的患者，如在重症监护病房的患者。这个 对一线抗生素出现耐药性，包括碳青霉烯类和最近引入的β-内酰胺/β- 内酰胺酶抑制剂组合，已导致使用效果降低的替代方案和 毒性增加。头孢地洛(FDC)是一种新型的含铁载体头孢菌素，具有体外抗肿瘤活性。 MDR-P。铜绿假单胞菌。这种抗生素模仿铜绿假单胞菌生长所需的铁结合分子，是 被称为TonB的细菌外膜上的蛋白质主动运输到周质空间 依赖受体(TBDR)。对FDC的耐药性与这些TBDR的表达缺失有关 铜绿假单胞菌临床分离株。此外，对收集到的铜绿假单胞菌基因组进行了分析。 FDC的批准发现，存在被预测会导致TBDR基因表达减少的突变 在碳青霉烯类耐药菌株中。利用种群分析图谱(PAP)，几株铜绿假单胞菌 带有tbdr突变的人对FDC表现出异质性耐药，或在抗生素时有一小部分细菌生长。 浓度高于临床耐药断点，尽管测试对标准敏感性敏感 测试。在两个主要的具体目标中，这项提议将调查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 暴露在FDC中的耐药性。在第一个目标中，将评估tbdr基因突变的流行率。 来自前瞻性观察的近千株耐碳青霉烯类铜绿假单胞菌 假单胞菌研究(POP)。这一途径的改变将与FDC敏感性测试结果联系在一起， PAP法评估铜绿假单胞菌异质性耐药及临床特征。在……里面 第二个目标，我们将调查了解和缓解阻力出现的策略 与TBDR突变相关。首先，基于纸片扩散的鉴定异抗分离物的方法将是 作为临床微生物学实验室的筛查试验而开发。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 临床上相关的药物浓度。这项提案将提供有关分配和 铜绿假单胞菌对FDC耐药相关突变的流行率。一种检测方法的发展 识别有耐药风险的菌株，并了解产生耐药性的机制 人类的药物暴露，可以形成在患者床边合理使用FDC治疗的基础。