Novel antimicrobials in fighting carbapenem-resistant Klebsiella pneumoniae

对抗耐碳青霉烯类肺炎克雷伯菌的新型抗菌药物

• 批准号: 10602594
• 负责人: Reen Wu
• 金额: $ 30万
• 依托单位: EFFECTORBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-05 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602594
• 关键词: Address; Air; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial Pneumonia; Blood; Blood specimen; Carbapenems; Caring; Cell Survival; Clinical; Colistin; Collection; Communities; Dose; Drug Kinetics; Engineering; Epithelial Cells; Exhibits; Frequencies; Half-Life; Healthcare; Hemolysis; Host Defense; In Vitro; Infection; Kinetics; Klebsiella; Klebsiella pneumoniae; Knockout Mice; Lead; Length; Liquid substance; Lung; Maximum Tolerated Dose; Measures; Membrane; Metabolic; Microbial Biofilms; Minimum Inhibitory Concentration measurement; Modeling; Modification; Morbidity - disease rate; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; Nasal Epithelium; Nosocomial Infections; Nosocomial pneumonia; Organism; Palate; Pathogenicity; Peptides; Permeability; Phase; Physiological; Pneumonia; Predisposition; Property; Proteins; Protocols documentation; Public Health; Recombinant Proteins; Recombinants; Resistance development; Respiratory Tract Infections; Rodent; Safety; Sepsis; Septicemia; Series; Serum; Small Business Innovation Research Grant; System; Testing; Therapeutic; Thick; Tissue Sample; Tissues; Toxic effect; Treatment Protocols; United States; Urine; airway epithelium; antibiotic resistant infections; antimicrobial; antimicrobial peptide; antimicrobial peptide LL-37; bactericide; beta-Lactamase; beta-Lactams; capsule; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; cytotoxicity; drug resistant pathogen; extensive drug resistance; fighting; global health; healthcare-associated infections; in vivo; in vivo Model; indexing; lead optimization; manufacture; meter; microbial; mortality; mouse model; multi-drug resistant pathogen; natural antimicrobial; next generation; novel; novel therapeutics; optimal treatments; pathogen; pathogenic bacteria; platelet function; pneumonia model; prevent; public health relevance; resistant Klebsiella pneumoniae; therapeutic candidate; therapy development

Project Summary/Abstract: Klebsiella is a common Gram-negative pathogen causing community-acquired bacterial pneumonia, and K. pneumoniae pneumonia is considered the most common cause of hospital-acquired pneumonia in the United States. K. pneumoniae is a difficult infection to treat because of the organism's thick capsule that is usually best treated with the last line antibiotic therapy such as carbapenems. However, carbapenem-resistant K. pneumoniae (CRKP), one of the carbapenem-resistant Enterobacteriaceae (CRE), is an emerging cause of antibiotic-resistant nosocomial infections associated with high rates of morbidity and mortality. New therapies in controlling CRKP-induced infections are urgently needed. Using recombinant protein and genetically modified mouse knockout models, we have demonstrated that the short palate, lung, nasal epithelium clone (PLUNC) 1 (SPLUNC1) contributes to pulmonary host defense against K. pneumoniae induced infection. A novel SPLUNC1- derived peptide from the antimicrobial motif of the SPLUNC1 protein, α4-Short, demonstrated more potent antibacterial properties than the full-length recombinant SPLUNC1 protein and in vivo efficacy in a murine model of respiratory infection. Based on additional modifications of α4-Short, we have recently developed a series of rationally engineered antimicrobial peptides (AMPs) that rapidly kill their microbial targets by permeabilizing bacterial membrane regardless of the specific metabolic state of the bacteria. One of our lead AMPs, A4-153, has demonstrated potent bactericidal activity against diverse difficult-to-treat multidrug resistant (MDR) pathogens, including CRKP. Exciting, A4-153 is active against many CRKP that have developed resistance to other membrane-active compounds, such as the natural AMP LL37 and colistin, an antibiotic of last resort. In addition, we have found a substantially lower tendency for bacteria to develop resistance to A4-153 compared to standard antibiotic agents and natural AMPs. Importantly, we found that similar to natural AMP LL37, A4-153 displayed no detectable hemolysis and could be safely administered to mouse lungs with very high concentrations. We propose in this SBIR application to explore the feasibility of using the newly developed A4- 153 to prevent CRKP-induced pneumonia by killing CRKP and eradicating the CRKP biofilm in the abiotic and biotic system using in vitro and in vivo models. The successful completion of the proposed aims in this Phase I application will prepare us for IND-enabling studies to be presented in a subsequent Phase II application, including multidose MTD, GLP toxicity in rodents and large animals, and initiation of GMP manufacturing.

项目摘要/摘要： 克雷伯菌（Klebsiella）是一种常见的革兰氏阴性病原体，导致社区获得的细菌性肺炎，K.。 肺炎肺炎被认为是联合医院获得医院肺炎的最常见原因 国家。 K.肺炎是一种很难治疗的感染，因为有机体的厚胶囊通常是最好的 用最后一系抗生素疗法（例如碳青霉）治疗。但是，耐碳青霉烯的K. 肺炎（CRKP）是耐碳青霉烯的肠杆菌科（CRE）之一，是新兴的原因 与高发病率和死亡率相关的抗生素耐药性医院感染。新疗法 迫切需要控制CRKP引起的感染。使用重组蛋白并经过一定的修饰 小鼠敲除模型，我们已经证明了短味，肺，鼻上皮克隆（Plunc）1 （Splunc1）有助于肺宿主防御肺炎肺炎诱导的感染。一种新颖的splunc1-- 从Splunc1蛋白的抗菌基序衍生的肽α4-Short表现出更有效的 抗菌特性比全长重组Splunc1蛋白和鼠模型中的体内效率 呼吸道感染。基于α4-short的其他修改，我们最近开发了一系列 合理设计的抗菌胡椒（AMP），通过通透性迅速杀死其微生物靶 细菌膜不管细菌的特定代谢状态如何。我们的主要放大器之一A4-153， 已经证明了针对难以治疗的多药（MDR）的潜水员的有效细菌活性（MDR） 病原体，包括CRKP。令人兴奋的是，A4-153对许多具有对的CRKP的活跃 其他膜活性化合物，例如天然AMP LL37和Colistin，是最后一个度假胜地的抗生素。在 此外，我们发现细菌具有对A4-153的抗性的趋势大大降低 标准抗生素剂和天然放大器。重要的是，我们发现类似于天然AMP LL37，A4-153 没有显示可检测的溶血，可以安全地施用至小鼠肺 浓度。我们建议在此SBIR应用中探索使用新开发的A4-的可行性 153，通过杀死CRKP并消除非生物剂中的CRKP生物膜，以防止CRKP诱导的肺炎 使用体外和体内模型的生物系统。在此阶段I的成功完成了拟议的目标 应用将使我们准备在随后的II期应用程序中提出的辅助研究， 包括啮齿动物和大动物中的多剂量MTD，GLP毒性，以及GMP制造的倡议。