Targeted delivery of antimicrobial peptides to intracellular bacterial pathogens

将抗菌肽靶向递送至细胞内细菌病原体

• 批准号: 1410987
• 负责人: Yoon Yeo
• 金额: $ 45万
• 依托单位: Purdue University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1410987&HistoricalAwards=false
• 关键词: Targeted; delivery; antimicrobial; peptides; intracellular

Non-technical Abstract:Intracellular bacterial infections are caused by bacteria that reside in host cells such as macrophages and multiply, avoiding detection and destruction by the host immune system. These infections are currently managed by oral or injectable antibiotics, which reach the infected cells only after spreading in the entire body. The therapeutic outcomes of traditional antibiotics treatment have not been satisfactory, because many antibiotics do not enter mammalian cells and access the intracellular pathogens. Moreover, the pathogens tend to develop resistance to the antibiotic treatment as a consequence of persistent suboptimal delivery of antibiotics. For the effective management of intracellular bacterial infections, there is a critical unmet need for new types of antimicrobials, which will effectively eradicate intracellular bacteria without inducing resistance, and an appropriate carrier system that will deliver the new agents specifically to the infected macrophages and the pathogens resident in the cells. In this research the PIs propose to develop new materials that may be of potential use in addressing intracellular bacterial infections. Specifically, the PIs will use positively charged peptides with potent antimicrobial activity to replace traditional antibiotics. The PIs will administer these peptides using pH-sensitive polysaccharides, which will take the peptides to the infected cells and help unpack them where the peptides are most needed. This project has the potential to bring about novel materials that may be of use relative to intractable intracellular infections. In addition, it will create a sustainable research platform for interdisciplinary collaborations and contribute to the next generation science education through active participation in institutional outreach service and joint summer research fellowship programs.Technical Abstract:Intracellular bacterial infections are currently managed by systemic administration of antibiotics. However, their therapeutic outcomes have not been satisfactory, because of the inefficient intracellular delivery of antibiotics and frequent emergence of bacterial resistance to the treatment. For the effective management of intracellular bacterial infections, there is a critical unmet need for new types of antimicrobials, which will treat persistent and multi-drug resistant intracellular bacterial infections, and an appropriate carrier system that will deliver the new agents specifically to the infected macrophages and the pathogens resident in the cells. Ideal treatment of intracellular pathogens should have low potential to induce bacterial resistance and be able to travel across the eukaryotic cell membrane and access pathogens residing inside the cells. To satisfy these requirements, the PIs will develop antimicrobial semi-nanoparticles (SNPs), consisting of (i) cationic antimicrobial peptides (CAMPs), a new class of antibacterial agents, and (ii) pH-sensitive polysaccharides, a carrier of CAMPs. The underlying hypothesis of this approach is that CAMPs will overcome the prevalent bacterial resistance through distinct mechanisms of action, and a pH-sensitive SNP system will offer a means to target the organs harboring infected cells (liver and spleen) and traffic CAMPs within the cells to access the intracellular pathogens. This research will bring about three outcomes with broad impact: medical benefits to patients with intractable intracellular infections; sustainable research platform for interdisciplinary collaborations; and outreach activities for advanced science education, including leadership in institutional service programs and implementation of joint summer research fellowships.

非技术摘要：细胞内细菌感染是由驻留在宿主细胞（如巨噬细胞）中的细菌引起的，并繁殖，避免被宿主免疫系统检测和破坏。这些感染目前通过口服或注射抗生素来控制，这些抗生素只有在扩散到整个身体后才能到达受感染的细胞。传统的抗生素治疗的治疗效果并不令人满意，因为许多抗生素不能进入哺乳动物细胞并进入细胞内的病原体。此外，由于抗生素的持续次优递送，病原体倾向于对抗生素治疗产生抗性。为了有效管理细胞内细菌感染，存在对新型抗微生物剂的关键未满足的需求，所述新型抗微生物剂将有效地根除细胞内细菌而不诱导抗性，以及适当的载体系统，所述载体系统将特异性地将新试剂递送至受感染的巨噬细胞和驻留在细胞中的病原体。在这项研究中，PI建议开发可能在解决细胞内细菌感染方面具有潜在用途的新材料。具体来说，PI将使用具有强效抗菌活性的带正电荷的肽来取代传统抗生素。PI将使用pH敏感的多糖来管理这些肽，这些多糖将肽带到受感染的细胞中，并帮助在最需要肽的地方解开它们。这个项目有可能带来新的材料，可能是相对于难治性细胞内感染的使用。此外，还将为跨学科合作创建一个可持续的研究平台，并通过积极参与机构外展服务和联合夏季研究奖学金计划为下一代科学教育做出贡献。技术摘要：细胞内细菌感染目前通过抗生素的全身管理来管理。然而，它们的治疗结果并不令人满意，因为抗生素的细胞内递送效率低，并且经常出现细菌对治疗的耐药性。为了有效管理细胞内细菌感染，存在对新型抗微生物剂的关键未满足的需求，所述新型抗微生物剂将治疗持续性和多重耐药性细胞内细菌感染，以及适当的载体系统，所述载体系统将特异性地将新试剂递送至感染的巨噬细胞和驻留在细胞中的病原体。细胞内病原体的理想治疗应该具有低的诱导细菌耐药性的潜力，并且能够穿过真核细胞膜并接近驻留在细胞内的病原体。为了满足这些要求，PI将开发抗菌半纳米颗粒（SNP），包括（i）阳离子抗菌肽（CAMP），一类新的抗菌剂，和（ii）pH敏感性多糖，CAMP的载体。这种方法的基本假设是，CAMPs将通过不同的作用机制克服普遍的细菌耐药性，并且pH敏感的SNP系统将提供靶向携带感染细胞的器官（肝脏和脾脏）并在细胞内运输CAMPs以接近细胞内病原体的手段。这项研究将带来三个具有广泛影响的成果：对难治性细胞内感染患者的医疗益处;跨学科合作的可持续研究平台;以及先进科学教育的外展活动，包括机构服务计划的领导和联合夏季研究奖学金的实施。