Maltoheptaose based nanotherapeutics for multidrug resistant bacterial infection

描述（由申请人提供）：抗生素耐药性具有重大的公共卫生风险，其中药物对微生物不再有效。曾经强大的抗微生物剂现在已经变得几乎无用，并且这种情况正在地球仪上迅速蔓延。该提案的目的是开发一种新的策略，用于靶向多重耐药细菌，由麦芽七糖（G7）作为靶向剂的治疗剂封装的纳米颗粒组成。关键假设是G7将极大地促进细菌细胞对纳米颗粒的摄取，而多价纳米颗粒将向细菌细胞中递送高局部剂量的治疗剂，以实现显著增强的抗生素效力。G7是一种麦芽糖糊精，是代谢活性的最大碳源，将被用作靶向剂，因为我们已经表明，它大大增加了细菌细胞对纳米颗粒的吸收，而对哺乳动物细胞的影响最小。此外，我们假设G7标记的纳米颗粒将大大提高抗生素治疗多重耐药细菌感染的疗效。在为期两年的项目期间，我们将综合和研究 抗菌药物包封的G7-脂质体和G7-胶束对多重耐药铜绿假单胞菌的体外抗菌活性。我们还将使用小鼠模型评估新纳米治疗剂的体内功效。这些研究的完成将证明，基于G7的纳米治疗剂将显著提高抗生素的治疗效果，并逆转铜绿假单胞菌的耐药性。该提案具有创新性 因为它代表了第一个使用营养素作为药物递送靶向策略的研究。该项目是重要的，因为这些研究的结果可以很容易地应用于其他系统，因此可以设想一个通用平台，用于增强多种治疗剂的递送，以治疗多重耐药细菌感染。

DESCRIPTION (provided by applicant): Antimicrobial resistance has a major public health risk where drugs are no longer effective against microorganisms. Once powerful antimicrobial agents have now become virtually useless, and the situation is spreading rapidly over the globe. The objective of this proposal is to develop a new strategy for targeting multidrug-resistant bacteria, composed of therapeutics-encapsulated nanoparticles with maltoheptaose (G7) as the targeting agent. The key hypothesis is that G7 will greatly facilitate the uptake of nanoparticles by bacterial cells whereas the multivalent nanoparticles will deliver high local doses of therapeutics into bacterial cells to achieve significantly enhanced antibiotic potency. G7, a maltodextrin that is the largest carbon source for metabolic activity, will be used as the targetin agent as we have shown that it drastically increased the uptake of nanoparticles by bacterial cells whereas it had minimal impact on mammalian cells. In addition, we hypothesize that G7-tagged nanoparticles will improve considerably the efficacy of antibiotics in treating multidrug-resistant bacterial infection. During the two-year project period, we will synthesize and study the antimicrobial activities of antibiotics-encapsulated G7-liposomes and G7-micelles against multidrug-resistant Pseudomonas aeruginosa in vitro. We will also evaluate the in vivo efficacy of the new nanotherapeutics using a mice model. The completion of these studies will demonstrate that G7-based nanotherapeutics will improve appreciably the therapeutic efficacy of antibiotics and revert the antimicrobial resistance of P. aeruginosa. The proposal is innovative because it represents the first study to use a nutrient as the targeting strategy for drug delivery The project is significant because results from these studies can be readily applied to other systems, thus a universal platform can be envisioned for enhancing the delivery of a diverse class of therapeutic agents to treat multidrug-resistant bacterial infections.