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.

Public Health Relevance

Drug-resistance has become a major public health risk causing drastic increases in healthcare cost as well as mortality and morbidity. This proposal focuses on developing a new platform for treating drug-resistant infections. The strategy uses a bacterial nutrient, maltoheptaose, as the bait to facilitate the entry of antibiotic-encapsulated nanoparticles into bacterial cells. This sweet Trojan horse will greatly enhance the therapeutic efficacy of antibiotics, making them effective in treating drug-resistant bacterial infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Xu, Zuoyu
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University of Massachusetts Lowell
Schools of Arts and Sciences
United States
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