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: 10053046
• 负责人: DAVID S WEISS
• 金额: $ 82.33万
• 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/10053046
• 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.

项目概要/摘要 抗生素耐药性是我们这个时代最严峻的医学挑战之一。这场危机使患者处于危险之中 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， 导致超过23,000人死亡。据估计，如果不采取重大行动，全球每年因 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。很遗憾， 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 基本上无法治疗。在这种情况下，采用抗生素组合来尝试克服 对个别药物有耐药性，但只是偶尔有效。组合何时以及为何起作用尚不清楚， 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。然而，我们现在表明，当结合起来时，两个 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 细胞对另一种细胞具有抗性[Band et al, Nature Microbiology, 2019]。因此，对多种 抗生素（“多重异质耐药性”）可被用作细菌的致命弱点，也是有效治疗的基础。 联合治疗方案。重要的是，该方法采用 FDA 批准的现有抗生素，并且可以 立即受聘于诊所。这种范式转变的联合治疗方法具有 可能产生重大转化影响，但必须首先受到广泛而彻底的质疑。在这里，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 针对多种异质抗性的组合测试。我们将进一步研究两者之间的关系 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。这项研究有 为临床医生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。