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: 10433990
• 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/10433990
• 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.

项目总结/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。这场危机使病人处于危险之中 无法治愈的细菌感染，并威胁到依赖抗生素的现代医学的重大进步 （移植、化疗等）。在美国，每年至少有200万例抗生素耐药性感染， 导致超过23,000人死亡据估计，如果不采取重大行动， 到2050年，这些感染将达到1 000万，超过癌症的预计死亡率。不幸的是， 一些细菌，包括碳青霉烯类耐药肠杆菌科（CRE）的特定分离株， 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有耐药性， 基本上无法治愈在这种情况下，使用抗生素的组合来试图克服这些问题。 对个别药物产生耐药性，但只是偶尔有效。何时以及为什么组合起作用尚不清楚， 因此临床医生缺乏合理的科学依据来选择抗生素以包括在这些方案中。 我们的研究揭示了一个意想不到的原则，与抗生素协同作用不同， 设计个性化的组合以杀死临床细菌分离株，包括泛耐药菌株。 这种联合治疗方法是基于异源耐药性，一种神秘的形式的抗生素耐药性， 其中细菌分离物具有抗性亚群，该抗性亚群可以在微生物存在下快速复制， 抗生素，而大多数易感人群被杀死。然而，我们现在表明，当结合起来，两个 给定菌株对之具有异源耐药性的抗生素杀死细菌，因为每种药物都抑制了细菌的亚群。 细胞对另一种具有抗性[Band et al，Nature Microbiology，2019]。因此，对多个 抗生素（“多重异源耐药性”）可以被用作细菌的阿基里斯之踵， 联合方案。重要的是，这种方法使用现有的FDA批准的抗生素， 立即在诊所工作。这种范式转变的联合治疗方法具有 潜在的重大翻译影响，但必须首先广泛和彻底的询问。这里我们 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， 测试对多种抗生素的异源耐药性这将允许选择和体外和体内 测试靶向多种异源抗性的组合。我们将进一步研究 多个异源抗性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 为临床医生提供合理和可预测的方法来处方有效的抗生素的潜力 联合治疗细菌感染，包括目前认为无法治疗的感染。