Exploitation of multiple heteroresistance for effective antibiotic combination therapy

利用多重异质耐药性进行有效的抗生素联合治疗

• 批准号: 10206015
• 负责人: DAVID S WEISS
• 金额: $ 80.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206015
• 关键词: Acinetobacter baumannii; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Cells; Cessation of life; Clinic; Clinical; Combined Antibiotics; Combined Modality Therapy; Exhibits; FDA approved; Future; Immunocompromised Host; In Vitro; Individual; Infection; Intermediate resistance; Kidney Transplantation; Klebsiella; Life; Malignant Neoplasms; Medical; Methods; Microbiology; Minor; Modeling; Modern Medicine; Nature; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Pneumonia; Population; Premature Infant; Regimen; Research; Resistance; Risk; Savings; Sepsis; Serratia; Stenotrophomonas; Systemic disease; Testing; Time; Transplant Recipients; Transplantation; Treatment Failure; Validation; Work; antibiotic resistant infections; bacterial resistance; bactericide; base; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; chemotherapy; clinical diagnostics; design; drug development; efficacy testing; experimental study; in vitro testing; in vivo; in vivo evaluation; intraperitoneal; kidney infection; mortality; mouse model; novel therapeutic intervention; novel therapeutics; pharmacokinetic model; pharmacokinetics and pharmacodynamics; resistant Klebsiella pneumoniae; resistant strain; routine screening; sound; synergism; targeted treatment; translational impact

Project Summary/Abstract Antibiotic resistance is one of the most serious medical challenges of our time. This crisis puts patients at risk of untreatable bacterial infections and threatens major advances of modern medicine that rely on antibiotics (transplants, chemotherapy, etc). There are at least 2 million antibiotic resistant infections each year in the US, leading to over 23,000 deaths. It is estimated that without significant action, worldwide annual mortality due to these infections will reach 10 million by 2050, surpassing the predicted mortality from cancer. Unfortunately, some bacteria, including specific isolates of carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant Acinetobacter baumannii (CRAB), are now resistant to all available antibiotics and are essentially untreatable. In such instances, combinations of antibiotics are employed to try to overcome the resistance to individual drugs, but are only sporadically effective. When and why combinations work is unclear, and clinicians therefore lack a sound scientific rationale for choosing antibiotics to include in these regimens. Our research has revealed an unexpected principle, distinct from antibiotic synergy, that can be used to design personalized combinations to kill clinical bacterial isolates including pan-resistant strains. This combination therapy approach is based on heteroresistance, an enigmatic form of antibiotic resistance in which a bacterial isolate harbors a resistant subpopulation that can rapidly replicate in the presence of an antibiotic, while the majority susceptible population is killed. However, we now show that when combined, two antibiotics to which a given strain is heteroresistant, kill the bacteria as each drug inhibits the subpopulation of cells resistant to the other [Band et al, Nature Microbiology, 2019]. Thus, heteroresistance towards multiple antibiotics (“multiple heteroresistance”) can be exploited as a bacterial Achilles' heel and the basis of effective combination regimens. Importantly, this method employs existing FDA-approved antibiotics and can be employed in the clinic immediately. This paradigm-shifting approach to combination therapy has the potential to have a major translational impact, but must first be broadly and thoroughly interrogated. Here, we propose to use a robust set of CRE and CRAB clinical isolates from a Georgia-based surveillance initiative to test for heteroresistance to a wide range of antibiotics. This will allow the selection and in vitro and in vivo testing of combinations targeting multiple heteroresistance. We will further study the relationship between the resistant subpopulations in multiple heteroresistant isolates, as well as performing dynamic flow experiments to determine the pharmacokinetics and pharmacodynamics of effective combinations. This research has the potential to provide clinicians with a rational and predictable method with which to prescribe effective antibiotic combinations to treat bacterial infections, including those currently considered untreatable.

项目摘要/摘要 抗生素耐药性是我们这个时代最严重的医疗挑战之一。这场危机使患者处于危险之中 不可治疗的细菌感染并威胁着依赖抗生素的现代医学的重大进展 （移植，化学疗法等）。在美国，每年至少有200万种抗生素感染， 导致超过23,000人死亡。据估计，没有采取重大行动，由于 到2050年，这些感染将达到1000万，超过了癌症的预测死亡率。很遗憾， 一些细菌，包括碳青霉烯的特定分离株（CRE）和 抗碳青霉苯甲酸杆菌（CRAB）（CRAB）现在对所有可用的抗生素具有抵抗力，并且是 本质上是不可治疗的。在这种情况下，采用抗生素的组合来克服 对单个药物的抵抗力，但仅偶发地有效。何时以及为什么组合起作用尚不清楚， 因此，临床医生缺乏选择抗生素包括在这些方案中的合理科学原理。 我们的研究揭示了一个意外的原理，与抗生素协同作用不同，可以使用 设计个性化组合以杀死包括泛抗菌菌株在内的临床细菌分离株。 这种组合疗法方法基于异位抗性，这是一种抗生素抗性的神秘形式 细菌分离出一种抗性亚群，可以在存在的情况下快速复制 抗生素，而大多数易感人群被杀。但是，我们现在表明，当组合时，两个 给定菌株具有异性抗性的抗生素，杀死细菌，因为每种药物都抑制了亚群的亚群 细胞对另一个[Band等人，自然微生物学，2019年]。那，对多个 可以将抗生素（“多种异质抗药性”）作为细菌性跟腱探索和有效的基础 组合方案。重要的是，该方法采用现有的FDA批准的抗生素，可以是 立即在诊所使用。这种组合疗法的这种范式转移方法具有 具有重大翻译影响的潜力，但必须首先受到广泛而彻底的询问。在这里，我们 提出从基于佐治亚州的监视计划中使用一组健壮的CRE和CRAB临床分离株的提议 测试与多种抗生素的异质抗性。这将允许选择，体外和体内 靶向多种异质抗性的组合测试。我们将进一步研究 多种异抗分离株中的抗性亚群，以及进行动态流动实验 确定有效组合的药代动力学和药效学。这项研究有 为临床医生提供有效且可预测的方法，以制备有效的抗生素 治疗细菌感染的组合，包括当前被认为不可治疗的人。