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：碳青霉烯耐药肠杆菌科（CRE）已被分类为一类