Development of Gene-Silencing Therapeutics for Pseudomonas aeruginosa

铜绿假单胞菌基因沉默疗法的开发

• 批准号: 10451560
• 负责人: David Elihu Greenberg
• 金额: $ 112.55万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451560
• 关键词: Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antisense Oligonucleotides; Automobile Driving; Bacteremia; Bacterial Infections; Biological; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Trials; Collaborations; Collection; Cystic Fibrosis; Development; Dose; Drug Kinetics; Drug resistance; Duchenne muscular dystrophy; Effectiveness; Enzyme-Linked Immunosorbent Assay; Enzymes; Essential Genes; FDA approved; Formulation; Frequencies; Gene Silencing; Gene Targeting; Genes; Goals; Immunocompromised Host; In Vitro; Infection; Investigation; Lead; Libraries; Life; Lipid A; Lung; Lung infections; Marketing; Messenger RNA; Methods; Minimum Inhibitory Concentration measurement; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mutation; Nosocomial Infections; Organism; Pathogenicity; Patients; Penetration; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Pneumonia; Positioning Attribute; Preclinical Testing; Process; Production; Protein Subunits; Proteins; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Regimen; Research; Resistance; Resistance development; Ribosomes; Risk; Rodent; Safety; Sepsis; Site; Specificity; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Toxicology; Transcript; Translational Repression; Translations; analytical method; antimicrobial; antimicrobial drug; chronic infection; combat; comparison control; cystic fibrosis patients; drug discovery; efficacy evaluation; efficacy study; fatty acid biosynthesis; healthcare-associated infections; improved; in vivo; indexing; innovation; interest; loss of function; mortality; multidrug-resistant Pseudomonas aeruginosa; novel; novel therapeutics; pathogen; pathogenic bacteria; pharmacokinetics and pharmacodynamics; phosphorodiamidate morpholino oligomer; pneumonia model; pre-clinical; preclinical development; prevent; resistance frequency; resistant strain; safety study; screening; small molecule; success; technology platform

PROJECT SUMMARY/ABSTRACT Gram-negative pathogens are becoming increasingly resistant to many antimicrobials. Furthermore, the pipeline for new antibiotics is small and new therapies are urgently needed. This can be especially problematic in patients who suffer from chronic infections or are immunocompromised. Multidrug-resistant Pseudomonas aeruginosa has been identified by the Centers for Disease Control and Prevention as a serious threat. P. aeruginosa causes healthcare associated infections in a variety of clinical settings and hosts, but is particularly devastating in patients with cystic fibrosis (CF). We have been interested in using antisense molecules called PPMOs as potential therapeutics in these infections. These molecules block messenger RNA and prevent the formation of the target protein. We have demonstrated that PPMOs can be used to target genes that are essential for Pseudomonas to grow, such as acpP, lpxC or rpsJ. We showed that blocking these proteins are essential for Pseudomonas to grow in vitro. We also showed that these PPMOs improve survival in mice that were infected with Pseudomonas. For this project, we propose to further characterize our lead PPMOs in a larger collection of Pseudomonas isolates, both antibiotic-sensitive and multidrug-resistant. In addition, efficacy studies will be performed in both models of pneumonia and bloodstream infection. This process will result in 2-4 PPMOs that will undergo further pre-clinical testing including toxicity, resistance, pharmacodynamic and pharmacokinetic studies. By the end of the proposed project, a lead PPMO will have undergone the needed pre-clinical testing for IND submission to the FDA. This innovative approach to developing novel antibiotics, particularly for P. aeruginosa, could help expand the increasingly shrinking classes of effective antibiotics that are used to treat these severe, life-threatening infections.

项目概要/摘要 革兰氏阴性病原体对许多抗菌药物的耐药性越来越强。此外，管道 对于新抗生素的需求很小，迫切需要新的疗法。这对患者来说尤其是个问题 患有慢性感染或免疫功能低下的人。多重耐药铜绿假单胞菌 已被疾病控制和预防中心认定为严重威胁。铜绿假单胞菌病因 各种临床环境和宿主中的医疗保健相关感染，但在以下领域尤其具有破坏性： 囊性纤维化（CF）患者。我们一直对使用称为 PPMO 的反义分子作为 这些感染的潜在治疗方法。这些分子阻断信使 RNA 并阻止形成 目标蛋白。我们已经证明 PPMO 可用于靶向对生命至关重要的基因 需要生长的假单胞菌，例如 acpP、lpxC 或 rpsJ。我们证明阻断这些蛋白质对于 假单胞菌在体外生长。我们还表明这些 PPMO 可以提高感染小鼠的存活率 与假单胞菌。对于这个项目，我们建议在更大的集合中进一步描述我们的主要 PPMO 的特征 假单胞菌分离株，对抗生素敏感且具有多重耐药性。此外，功效研究将 在肺炎和血流感染模型中进行。此过程将产生 2-4 个 PPMO， 将接受进一步的临床前测试，包括毒性、耐药性、药效学和药代动力学 研究。到拟议项目结束时，牵头 PPMO 将接受所需的临床前测试 向 FDA 提交 IND。这种开发新型抗生素的创新方法，特别是针对 P. 铜绿假单胞菌，可以帮助扩大用于治疗的日益缩小的有效抗生素类别 这些严重的、危及生命的感染。