Host defense-stimulating macrocyclic peptides for treatment of MDR bacterial infections

用于治疗耐多药细菌感染的宿主防御刺激大环肽

• 批准号: 9267426
• 负责人: Andre J. Ouellette
• 金额: $ 104.24万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267426
• 关键词: ADME Study; Acute Toxicity Tests; Animal Model; Antibiotic Resistance; Antibiotics; Attenuated; Bacteria; Bacterial Infections; Binding; Biochemical; Biological Markers; Carbapenems; Characteristics; Collaborations; Complement; Complex; Cyclic GMP; Cyclic Peptides; Defensins; Development; Dose; Drug Kinetics; Engineering; Enterobacteriaceae; Enterobacteriaceae Infections; Epidemic; Escherichia coli; Evaluation; Excretory function; Goals; Hand; Host Defense; Immune; Immune response; Immune system; Immunity; In Vitro; Inbred BALB C Mice; Infection; Injectable; Kilogram; Kinetics; Klebsiella; Klebsiella pneumonia bacterium; Knowledge; Label; Lactamase; Lead; Leukocytes; Lymphocyte Suppression; Maximum Tolerated Dose; Mediating; Mediator of activation protein; Membrane; Metabolism; Methods; Modeling; Multi-Drug Resistance; Mus; Oryctolagus cuniculus; Pan Genus; Penicillins; Peptides; Periodicity; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Plant Leaves; Plants; Production; Property; Public Health; Publishing; Rattus; Recombinants; Reporting; Research; Resistance; Resistance profile; Resort; Selection Criteria; Sepsis; Series; Solubility; Solvents; System; Technology; Testing; Therapeutic; Therapeutic Uses; Tobacco; Toxic effect; VDAC1 gene; Work; absorption; acute toxicity; analog; antimicrobial; apoptosis in lymphocytes; bacterial resistance; base; beta-Lactamase; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; carbapenemase; chemotherapy; comparative; cost; cytokine; data resource; design; efflux pump; experience; immunoregulation; in vivo; innovation; lead series; microbicide; multi-drug resistant pathogen; nonhuman primate; novel; novel therapeutics; pathogen; pathogenic bacteria; peptide drug; pre-clinical; preclinical development; prototype; resistance factors; resistance mechanism; response; retinal rods; septic; success; theta-defensin

The emergence of carbapenem-resistant Enterobacteriaceae (CRE) has created a major and urgent public health threat, because carbapenems are drugs of last resort for treatment of infections caused by a growing number of multidrug resistant (MDR) bacterial pathogens. The objective of this project is to develop a novel therapeutic for treatment of CRE infections by capitalizing on the unique host defense-modulating properties of macrocyclic theta (θ)-defensins in animal models of infection. Preliminary studies provide evidence that θ- defensins and engineered analogs can be developed as agents to treat carbapenemase-producing Klebsiella pneumoniae (KPC-Kp). Pharmacokinetic (PK) studies and analyses of cytokine responses in θ-defensin- treated septic mice demonstrate that these novel cyclic peptides augment host responses to bacteria by modu- lating the release of proinflammatory mediators and attenuating NFκB activation, enhancing host defense in a manner independent of the pathogen’s antibiotic resistance profile. In Aim 1, we will identify a lead therapeutic peptide (LTP) from a series of macrocyclic peptides bioinspired by θ-defensins. Criteria for selection of the LTP will include a) efficacy in the mouse KPC-Kp sepsis model, b) peptide solubility and stability, c) lack of acute toxicity, d) ease of synthetic production, e) extent of bacterial burden reduction in vivo, f) pharmacody- namic (PD) response of additional correlative biomarkers, g) dose-dependent efficacy in a second infection model, and h) single-dose PK. Since half of the lead series of peptides is already in hand, down selection to the LTP can be completed rapidly and certainly within the mandated two-year period. In Aim 2, we will perform single and multiple-dose PK of injectable LTP in mice and NZW rabbits, and use 14C-labeled LTP to define peptide absorption, distribution, metabolism, and excretion (ADME) in mice. Preliminary toxicity studies will be performed to determine maximum tolerated dose in mice. In Aim 3, we propose to express a precyclic-LTP in E. coli using the pET-28a system; the precyclic product is efficiently cyclized in vitro with the recently discov- ered cycloconvertase that produces θ-defensins in vivo. We will also produce cyclic LTP using a robust re- combinant expression system in planta, in collaboration with one of the project’s commercial partners. These studies will capitalize on recent success in producing fully cyclized θ-defensin in tobacco leaf. Collectively, the results of Aim 3 studies will provide a system for efficient, low cost production of the LTP. The significance of the project lies in its promise for development of a unique peptide-based therapeutic for treatment of CRE in- fections. We hypothesize that peptide-based immunomodulatory therapeutics will offer advantages for CRE treatment over agents that seek to target a particular resistance component or function solely as microbicides, representing an innovative approach. Based on published work, existing preliminary data, resources already in place, and established corporate partnerships, we believe the proposed research plan has great potential to introduce a paradigm changing approach for treating CRE and other MDR pathogens.

碳青霉烯耐药肠杆菌科（CRE）的出现已经引起了重大和紧迫的公众关注