Targeted delivery of antimicrobial peptides to intracellular bacterial pathogens

非技术摘要：细胞内细菌感染是由寄主细胞中的细菌引起的，例如巨噬细胞并繁殖，避免了宿主免疫系统的检测和破坏。这些感染目前是通过口服或注射抗生素来管理的，只有在全身传播后才能到达受感染的细胞。传统的抗生素治疗效果并不令人满意，因为许多抗生素不会进入哺乳动物细胞并接触到细胞内的病原体。此外，由于抗生素的持续次优输送，病原体往往对抗生素治疗产生抗药性。对于细胞内细菌感染的有效管理，迫切需要新型抗菌剂和适当的载体系统，这些抗菌剂将有效地根除细胞内细菌而不会产生耐药性，并且将专门将新药物输送到受感染的巨噬细胞和驻留在细胞内的病原体。在这项研究中，PI建议开发新的材料，这些材料可能在解决细胞内细菌感染问题上具有潜在的用途。具体地说，PI将使用具有强大抗菌活性的正电荷多肽来取代传统抗生素。PI将使用对pH敏感的多糖来管理这些多肽，这将把这些多肽带到受感染的细胞，并帮助他们在最需要多肽的地方拆包。这个项目有可能带来新的材料，这些材料可能对难治性细胞内感染有用。此外，它还将通过积极参与机构外展服务和联合暑期研究奖学金计划，为跨学科合作创造一个可持续的研究平台，并为下一代科学教育做出贡献。技术摘要：目前，细胞内细菌感染是由系统的抗生素管理的。然而，它们的治疗效果并不令人满意，因为抗生素在细胞内的输送效率低下，而且经常出现细菌对治疗的耐药性。为了有效地管理细胞内细菌感染，迫切需要新型抗菌剂和适当的载体系统，这些药物将治疗持久的和多药耐药的细胞内细菌感染，并将新药物专门输送到受感染的巨噬细胞和驻留在细胞内的病原体。理想的细胞内病原体治疗应该具有诱导细菌耐药性的低潜力，并能够穿过真核细胞膜并接触驻留在细胞内的病原体。为了满足这些要求，PIs将开发抗菌半纳米颗粒(SNPs)，包括(I)阳离子抗菌肽(CAMP)，一种新型抗菌剂，以及(Ii)pH敏感的多糖，cAMP的载体。这种方法的基本假设是，cAMP将通过不同的作用机制克服普遍存在的细菌耐药性，而对pH敏感的SNP系统将提供一种手段，针对含有受感染细胞的器官(肝和脾)和细胞内的交通cAMP来访问细胞内的病原体。这项研究将带来三个具有广泛影响的成果：为顽固性细胞内感染患者带来医疗利益；为跨学科合作提供可持续的研究平台；以及高级科学教育的外联活动，包括在机构服务计划中的领导和联合夏季研究奖学金的实施。

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.