Targeted delivery of antimicrobial peptides to intracellular bacterial pathogens

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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.