Novel Strategies for Antibiotic Combinations to Combat Gram-negative Superbugs

抗生素组合对抗革兰氏阴性超级细菌的新策略

• 批准号: 10530652
• 负责人: Jurgen Bernd Bulitta
• 金额: $ 76.41万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-20 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530652
• 关键词: Abdominal Infection; Affinity; Antibiotics; Aztreonam; Bacteria; Binding; Binding Proteins; Biological Assay; CRISPR/Cas technology; Carbapenems; Ceftazidime; Cell Membrane Permeability; Chromosomes; Classification; Clinic; Clinical; Clinical Trials; Combined Antibiotics; Data; Data Set; Disease Outbreaks; Dose; Drug Combinations; Drug Kinetics; Drug resistance; Engineering; Escherichia coli; Extended-spectrum β-lactamase; Face; Fiber; Future; Genetic Engineering; Genomics; Goals; Health; Hospitals; Human; Immune system; Immunocompetent; Impairment; In Vitro; Infection; Intra-abdominal; Klebsiella pneumoniae; Mediating; Medical; Membrane; Modeling; Molecular; Mus; Mutation; Nevada; Patients; Penetration; Penicillin-Binding Proteins; Permeability; Pharmaceutical Preparations; Pharmacology; Plasmids; Polymyxin B; Polymyxin Resistance; Polymyxins; Prevention; Public Health; Regimen; Reporting; Resistance; Safety; Sepsis; Site; Superbug; System; Techniques; Testing; Therapeutic; Time; Translations; Urinary tract; VDAC1 gene; Validation; beta-Lactamase; beta-Lactams; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; carbapenemase; colistin resistance; combat; data integration; design; dosage; global health; improved; inhibitor; innovation; insight; mortality; novel; novel strategies; pathogen; pharmacodynamic model; pneumonia model; prevent; prospective; receptor; receptor binding; resistance gene; resistance mechanism; resistant Klebsiella pneumoniae; resistant strain; respiratory; transcriptomics

Project Summary/Abstract: Carbapenem-Resistant Enterobacteriaceae (CRE) have been classified as an urgent public health threat in the US and around the globe. New Delhi Metallo-β-lactamases (NDM) producing CRE are particularly concerning as they have rapidly spread worldwide and can efficiently co- exist with a plethora of Gram-negative resistance determinants including Extended Spectrum β-lactamases (ESBLs), carbapenemases, and polymyxin resistance genes. We have reported the first US case of polymyxin- and carbapenem-resistant E. coli producing New Delhi Metallo-beta-lactamase (NDM-5) together with mobile colistin resistance (MCR-1) in a patient. The recent report of pan-drug-resistant (PDR), K. pneumoniae (NDM-1, ESBLs, and polymyxin resistance determinants), from a patient in Nevada further highlights that it may be only a matter of time until hospitals in the US and worldwide face an outbreak of these Gram-negative ‘superbugs’. It is critical to prepare therapeutics for the future occurrence of NDM strains which harbor a diverse array of resistance determinants. Our Central Hypothesis is that rationally optimized antibiotic combination dosing strategies will achieve extensive killing and prevent emergence of resistance against of NDM-producing Enterobactericeae. Our preliminary studies provide compelling evidence in support of our innovative combinations. We established the first highly efficient cassette assay to assess target site penetration of β-lactams in the presence of polymyxins, the first dataset on β-lactam receptor binding in K. pneumoniae, and show that new 4-drug combination regimens eradicated NDM and ESBL co-producing K. pneumoniae and prevented resistance. In Aim 1, we will create genetically engineered strains, as well as assess the target site penetration and receptor binding of β-lactam antibiotics and β-lactamase inhibitors, and the enhanced penetration in presence of polymyxins. In Aim 2, in vitro pharmacokinetic/pharmacodynamics models, including the dynamic Hollow Fiber Infection Model, will evaluate optimized dosing strategies for 3- and 4-drug combinations by profiling the time course of bacterial killing, suppression of resistance, and persister eradication. Genomics and transcriptomics will be utilized to understand why monotherapies and non-optimized combinations failed with resistance. In Aim 3, our latest Quantitative and Systems Pharmacology (QSP) modelling approach will guide translation across all experimental tiers. Prospective validation of these novel optimal combination dosing strategies will be completed in murine pneumonia models with an intact and impaired immune system. This will yield innovative combination dosage regimens against pandrug-resistant CRE that can suppress resistance. Thus, this project will address an urgent, global medical need. This project will provide the first mechanistically informed, rationally optimized and prospectively validated combination dosing strategies of available antibiotics against resistant Gram-negatives that will be ready for testing in future clinical trials.

项目摘要/摘要：耐碳苯甲酸肠杆菌科（CRE）已归类为 美国和全球的紧急公共卫生威胁。新德里金属β-内酰胺酶（NDM） 生产CRE特别关注，因为它们在全球范围内迅速传播，并且可以有效地共同进行 存在多种革兰氏阴性抗性决定包括扩展的β-内酰胺酶的决定 （ESBL），碳二烯酶和多粘毒素耐药基因。我们已经报告了第一个美国的案例 多霉菌素和碳苯甲甲状腺大肠杆菌产生新德里Metallo-beta-lactamase（NDM-5） 与患者中的移动结肠毒素耐药性（MCR-1）一起。最近的抗药药（PDR）的报告， K.肺炎（NDM-1，ESBLS和多粘蛋白耐药性确定剂），内华达州的患者进一步 强调，直到美国和全球的医院面临爆发的爆发，可能只是时间问题 这些革兰氏阴性的“超级细菌”。为未来的NDM准备疗法至关重要 具有一系列阻力决定者的菌株。我们的中心假设是合理地 优化的抗生素组合剂量策略将实现广泛的杀戮并防止出现 抵抗产生NDM的肠杆菌科。我们的初步研究提供了引人注目的 支持我们创新组合的证据。我们建立了第一个高效的盒式盒式测定 为了评估β-内酰胺的靶位位点在存在多碳素的情况下，这是β-内酰胺上的第一个数据集 受体结合在K.肺炎中，并表明新的4药物组合方案是辐射NDM和 ESBL共同生产K.肺炎并防止耐药性。在AIM 1中，我们将一般创建 工程菌株以及评估β-内酰胺抗生素的目标位点渗透和受体结合 和β-内酰胺酶的抑制剂，以及在存在多聚浆素的情况下的渗透率增强。在AIM 2中，体外 药代动力学/药效学模型，包括动态空心纤维感染模型，将 通过分析细菌的时间过程，评估3和4药物组合的优化剂量策略 杀人，抑制抵抗和毅力消除。基因组学和转录组学将用于 理解为什么单一疗法和非优化组合因电阻而失败。在AIM 3中，我们的最新 定量和系统药理学（QSP）建模方法将指导所有人的翻译 实验层。这些新颖的最佳组合剂量策略的预期验证将是 以完整且受损的免疫抑制系统的鼠肺炎模型完成。这将产生 具有抗药性CRE的创新组合剂量方案可以抑制抗药性。 那，该项目将满足紧急的全球医疗需求。该项目将提供第一个 机械知识，合理优化和前瞻性验证的组合剂量策略 可用的抗生素可抵抗抗性革兰氏阴性阴性，可以在以后的临床试验中进行测试。