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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要抗生素耐药性是我们这个时代最严重的医学挑战之一，这场危机使患者面临风险。无法治疗的细菌感染，并威胁到依赖抗生素的现代医学的重大进步（移植、化疗等）美国每年至少有 200 万例抗生素耐药感染。据估计，如果不采取重大行动，全球每年因该病死亡的人数将超过 23,000 人。到 2050 年，这些感染人数将达到 1000 万，超过了癌症死亡率的预测。一些细菌，包括耐碳青霉烯类肠杆菌科 (CRE) 的特定分离株和碳青霉烯类耐药鲍曼不动杆菌（CRAB）现在对所有可用的抗生素都具有耐药性，并且在这种情况下，基本上无法治疗，可以使用抗生素组合来尝试克服这种情况。对单一药物有耐药性，但联合用药何时有效以及为何有效尚不清楚。因此，人们缺乏合理的科学依据来选择将抗生素纳入这些治疗方案中。我们的研究揭示了一个意想不到的原理，与抗生素协同作用不同，可以使用设计个性化组合来杀死临床细菌分离株，包括泛耐药菌株。这种联合治疗方法基于异质耐药性，这是一种神秘的抗生素耐药性形式。其中细菌分离株含有耐药亚群，可以在存在细菌的情况下快速复制抗生素，而大多数易感人群被杀死。但是，我们现在表明，将两者结合起来。特定菌株具有异质抗药性的抗生素会杀死细菌，因为每种药物都会抑制细菌亚群细胞对另一种细胞的耐药性[Band et al, Nature Microbiology, 2019]。抗生素（“多重异质耐药性”）可被用作细菌的致命弱点和有效性的基础重要的是，该方法采用 FDA 批准的现有抗生素，并且可以这种改变范式的联合治疗方法立即应用于临床。可能产生重大转化影响，但首先必须进行广泛而彻底的质疑。建议使用来自佐治亚州监测计划的一组强大的 CRE 和 CRAB 临床分离株来测试对多种抗生素的异质耐药性，这将允许在体外和体内进行选择。我们将进一步研究针对多种异质抗性的组合的测试。多个异质耐药菌株中的耐药亚群，以及进行动态流实验确定有效组合的药代动力学和药效学。有可能为上级提供合理且可预测的方法来开出有效的抗生素联合治疗细菌感染，包括目前认为无法治疗的细菌感染。